Acute kidney injury in neonates with hypoxic ischemic encephalopathy based on serum creatinine decline compared to KDIGO criteria.

BACKGROUND: Neonates with hypoxic ischemic encephalopathy receiving therapeutic hypothermia (HIE + TH) are at risk for acute kidney injury (AKI). The standardized Kidney Disease Improving Global Outcomes (KDIGO) criteria identifies AKI based on a rise in serum creatinine (SCr) or reduced urine output. This definition is challenging to apply in neonates given the physiologic decline in SCr during the first week of life. Gupta et al. proposed alternative neonatal criteria centered on rate of SCr decline. This study aimed to compare the rate of AKI based on KDIGO and Gupta in neonates with HIE and to examine associations with mortality and morbidity. METHODS: A retrospective review was performed of neonates with moderate to severe HIE + TH from 2008 to 2020 at a single center. AKI was assessed in the first 7 days after birth by KDIGO and Gupta criteria. Mortality, brain MRI severity of injury, length of stay, and duration of respiratory support were compared between AKI groups. RESULTS: Among 225 neonates, 64 (28%) met KDIGO, 69 (31%) neonates met Gupta but not KDIGO, and 92 (41%) did not meet either definition. Both KDIGO-AKI and GuptaOnly-AKI groups had an increased risk of the composite mortality and/or moderate/severe brain MRI injury along with longer length of stay and prolonged duration of respiratory support compared to those without AKI. CONCLUSIONS: AKI in neonates with HIE + TH was common and varied by definition. The Gupta definition based on rate of SCr decline identified additional neonates not captured by KDIGO criteria who are at increased risk for adverse outcomes. Incorporating the rate of SCr decline into the neonatal AKI definition may increase identification of clinically relevant kidney injury in neonates with HIE + TH.

Epidemiology of acute kidney injury in children: a report from the 26th Acute Disease Quality Initiative (ADQI) consensus conference.

The nephrology and critical care communities have seen an increase in studies exploring acute kidney injury (AKI) epidemiology in children. As a result, we now know that AKI is highly prevalent in critically ill neonates, children, and young adults. Furthermore, children who develop AKI experience greater morbidity and higher mortality. Yet knowledge gaps still exist that suggest a more comprehensive understanding of AKI will form the foundation for future efforts designed to improve outcomes. In particular, the areas of community acquired AKI, AKI in non-critically ill children, and cohorts from low-middle income countries have not been well studied. Longer-term functional outcomes and patient-centric metrics including social determinants of health, quality of life, and healthcare utilization should be the foci of the next phase of scholarship. Current definitions identify AKI-based upon evidence of dysfunction which serves as a proxy for injury; biomarkers capable of identifying injury as it occurs are likely to more accurately define populations with AKI. Despite the strength of the association, the causal and mechanistic relationships between AKI and poorer outcomes remain inadequately examined. A more robust understanding of the relationship represents a potential to identify therapeutic targets. Once established, a more comprehensive understanding of AKI epidemiology in children will allow investigation of preventive, therapeutic, and quality improvement interventions more effectively.

Advances in pediatric acute kidney injury pathobiology: a report from the 26th Acute Disease Quality Initiative (ADQI) conference.

BACKGROUND: In the past decade, there have been substantial advances in our understanding of the pathobiology of pediatric acute kidney injury (AKI). In particular, animal models and studies focused on the relationship between kidney development, nephron number, and kidney health have identified a number of heterogeneous pathophysiologies underlying AKI. Despite this progress, gaps remain in our understanding of the pathobiology of pediatric AKI. METHODS: During the 26th Acute Disease Quality Initiative (ADQI) Consensus conference, a multidisciplinary group of experts discussed the evidence and used a modified Delphi process to achieve consensus on recommendations for opportunities to advance translational research in pediatric AKI. The current state of research understanding as well as gaps and opportunities for advancement in research was discussed, and recommendations were summarized. RESULTS: Consensus was reached that to improve translational pediatric AKI advancements, diverse teams spanning pre-clinical to epidemiological scientists must work in concert together and that results must be shared with the community we serve with patient involvement. Public and private research support and meaningful partnerships with adult research efforts are required. Particular focus is warranted to investigate the pediatric nuances of AKI, including the effect of development as a biological variable on AKI incidence, severity, and outcomes. CONCLUSIONS: Although AKI is common and associated with significant morbidity, the biologic basis of the disease spectrum throughout varying nephron developmental stages remains poorly understood. An incomplete understanding of factors contributing to kidney health, the diverse pathobiologies underlying AKI in children, and the historically siloed approach to research limit advances in the field. The recommendations outlined herein identify gaps and outline a strategic approach to advance the field of pediatric AKI via multidisciplinary translational research.

Pediatric AKI in the real world: changing outcomes through education and advocacy-a report from the 26th Acute Disease Quality Initiative (ADQI) consensus conference.

BACKGROUND: Acute kidney injury (AKI) is independently associated with increased morbidity and mortality across the life course, yet care for AKI remains mostly supportive. Raising awareness of this life-threatening clinical syndrome through education and advocacy efforts is the key to improving patient outcomes. Here, we describe the unique roles education and advocacy play in the care of children with AKI, discuss the importance of customizing educational outreach efforts to individual groups and contexts, and highlight the opportunities created through innovations and partnerships to optimize lifelong health outcomes. METHODS: During the 26th Acute Disease Quality Initiative (ADQI) consensus conference, a multidisciplinary group of experts discussed the evidence and used a modified Delphi process to achieve consensus on recommendations on AKI research, education, practice, and advocacy in children. RESULTS: The consensus statements developed in response to three critical questions about the role of education and advocacy in pediatric AKI care are presented here along with a summary of available evidence and recommendations for both clinical care and research. CONCLUSIONS: These consensus statements emphasize that high-quality care for patients with AKI begins in the community with education and awareness campaigns to identify those at risk for AKI. Education is the key across all healthcare and non-healthcare settings to enhance early diagnosis and develop mitigation strategies, thereby improving outcomes for children with AKI. Strong advocacy efforts are essential for implementing these programs and building critical collaborations across all stakeholders and settings.

Impact of the Magnitude and Timing of Fluid Overload on Outcomes in Critically Ill Children: A Report From the Multicenter International Assessment of Worldwide Acute Kidney Injury, Renal Angina, and Epidemiology (AWARE) Study.

OBJECTIVES: With the recognition that fluid overload (FO) has a detrimental impact on critically ill children, the critical care nephrology community has focused on identifying clinically meaningful targets for intervention. The current study aims to evaluate the epidemiology and outcomes associated with FO in an international multicenter cohort of critically ill children. The current study also aims to evaluate the association of FO at predetermined clinically relevant thresholds and time points (FO ≥ 5% and FO ≥ 10% at the end of ICU days 1 and 2) with outcomes. DESIGN: Prospective cohort study. SETTING: Multicenter, international collaborative of 32 pediatric ICUs. PATIENTS: A total of 5,079 children and young adults admitted consecutively to pediatric ICUs as part of the Assessment of the Worldwide Acute Kidney Injury, Renal Angina and Epidemiology Study. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The FO thresholds at the time points of interest occurred commonly in the cohort (FO ≥ 5%Day1 in 38.1% [ n = 1753], FO ≥ 10%Day1 in 11.7% [ n = 537], FO ≥ 5%Day2 in 53.3% [ n = 1,539], FO ≥ 10%Day2 in 25.1% [ n = 724]). On Day1, multivariable modeling demonstrated that FO ≥ 5% was associated with fewer ICU-free days, and FO ≥ 10% was associated with higher mortality and fewer ICU and ventilator-free days. On multivariable modeling, FO-peak, Day2 FO ≥ 5%, and Day2 FO ≥ 10% were associated with higher mortality and fewer ICU and ventilator-free days. CONCLUSIONS: This study found that mild-to-moderate FO as early as at the end of ICU Day1 is associated with adverse outcomes. The current study fills an important void in the literature by identifying critical combinations of FO timing and quantity associated with adverse outcomes (FO ≥ 5%Day1, FO ≥10%Day1, FO ≥ 5%Day2, and FO ≥ 10%Day2). Those novel findings will help guide the development of interventional strategies and trials targeting the treatment and prevention of clinically relevant FO.

Impact of a clinical pathway on acute kidney injury in patients undergoing heart transplant.

BACKGROUND: To evaluate the impact of a clinical pathway on the incidence and severity of acute kidney injury in patients undergoing heart transplant. METHODS: This was a 2.5-year retrospective evaluation using 3 years of historical controls within a cardiac intensive care unit in an academic children's hospital. Patients undergoing heart transplant between May 27, 2014, and April 5, 2017 (pre-pathway) and May 1, 2017, and November 30, 2019 (pathway) were included. The clinical pathway focused on supporting renal perfusion through hemodynamic management, avoiding or delaying nephrotoxic medications, and providing pharmacoprophylaxis against AKI. RESULTS: There were 57 consecutive patients included. There was an unadjusted 20% reduction in incidence of any acute kidney injury (p = .05) and a 17% reduction in Stage 2/3 acute kidney injury (p = .09). In multivariable adjusted analysis, avoidance of Stage 2/3 acute kidney injury was independently associated with the clinical pathway era (AOR -1.3 [95% CI -2.5 to -0.2]; p = .03), achieving a central venous pressure of or less than 12 mmHg (AOR -1.3 [95% CI -2.4 to -0.2]; p = .03) and mean arterial pressure above 60 mmHg (AOR -1.6 [95% CI -3.1 to -0.01]; p = .05) in the first 48 h post-transplant, and older age at transplant (AOR - 0.2 [95% CI -0.2 to -0.06]; p = .002). CONCLUSIONS: This report describes a renal protection clinical pathway associated with a reduction in perioperative acute kidney injury in patients undergoing heart transplant and highlights the importance of normalizing perioperative central venous pressure and mean arterial blood pressure to support optimal renal perfusion.

Post-operative Morbidity and Mortality After Fontan Procedure in Patients with Heterotaxy and Other Situs Anomalies.

Heterotaxy is a complex, multisystem disorder associated with single ventricle heart disease and decreased survival. Ciliary dysfunction is common in heterotaxy and other situs abnormalities (H/SA) and may increase post-operative complications. We hypothesized that patients with H/SA have increased respiratory and renal morbidities and increased in-hospital mortality after Fontan procedure. We queried the Pediatric Health Information System database for hospitalizations with ICD-9/10 codes for Fontan procedure in patients aged 1 through 11 years from 2004 to 2019. H/SA was identified by codes for dextrocardia, situs inversus, asplenia/polysplenia, or atrial isomerism and compared to non-H/SA controls. Outcomes were in-hospital mortality or heart transplantation, ECMO, hemodialysis, length of stay (LOS), and mechanical ventilation or vasoactive medication use ≥ 4 days. We adjusted estimates with multivariable logistic regression. Of 7897 patients at 50 centers, 1366 (17%) met criteria for H/SA. H/SA had worse outcomes for all study measures: death/transplantation (1.9 vs 1.1%, OR 1.74 (95% CI 1.01-3.03); p = 0.047), ECMO (3.7 vs 2.3%, OR 1.74 (1.28-2.35); p < 0.001), hemodialysis (2.1 vs 1.2%, OR 1.66 (1.06-2.59); p = 0.026), prolonged mechanical ventilation (13.2% vs 7.6%, OR 1.85 (1.53-2.25); p < 0.001) and vasoactive medication use (29.4 vs 19.7%, OR 1.65 (1.43-1.90), and longer LOS (11 (8-17) vs 9 (7-14) days; p < 0.001). H/SA is associated with increased cardiovascular, renal, and respiratory morbidity, as well as in-hospital mortality after Fontan procedure. Attention to renal and respiratory needs may improve outcomes in this difficult population. The relationship between ciliary dysfunction and lung and renal morbidity should be explored further.

Cumulative Application of Creatinine and Urine Output Staging Optimizes the Kidney Disease: Improving Global Outcomes Definition and Identifies Increased Mortality Risk in Hospitalized Patients With Acute Kidney Injury.

OBJECTIVES: Acute kidney injury is diagnosed according to creatinine and urine output criteria. Traditionally, both are applied, and a severity stage (1-3) is conferred based upon the more severe of the two; information from the other criteria is discarded. Physiologically, however, rising creatinine and oliguria represent two distinct types of renal dysfunction. We hypothesized that using the information from both criteria would more accurately characterize acute kidney injury severity and outcomes. DESIGN: Prospective cohort study. SETTING: Multicenter, international collaborative of ICUs. PATIENTS: Three thousand four hundred twenty-nine children and young adults admitted consecutively to ICUs as part of the Assessment of the Worldwide Acute Kidney Injury, Renal Angina and Epidemiology Study. MEASUREMENTS AND MAIN RESULTS: The Kidney Disease: Improving Global Outcomes creatinine and urine output acute kidney injury criteria were applied sequentially, and the two stages were summed, generating an Acute Kidney Injury (AKI) Score ranging from 1 to 6. The primary outcome was 28-day mortality; secondary outcomes were time until ICU discharge and nonrecovery from acute kidney injury. Models considered associations with AKI Score, assessing the relationship unadjusted and adjusted for covariates. Twenty-eight-day mortality and nonrecovery from acute kidney injury were modeled using logistic regression. For 28-day ICU discharge, competing risks analysis was performed. Although AKI Scores 1-3 had similar mortality to no Acute Kidney Injury, AKI Scores 4-6 were associated with increased mortality. Relative to No Acute Kidney Injury, AKI Scores 1-6 were less likely to be discharged from the ICU within 28 days. Relative to AKI Score 1, AKI Scores 2-6 were associated with higher risk of nonrecovery. Within the traditional Kidney Disease: Improving Global Outcomes Stage 3 acute kidney injury cohort, when compared with AKI Score 3, AKI Scores 4-6 had increased mortality, AKI Scores 5-6 had prolonged time to ICU discharge, and AKI Score 6 experienced higher nonrecovery rates. CONCLUSIONS: Cumulative application of the creatinine and urine output criteria characterizes renal excretory and fluid homeostatic dysfunction simultaneously. This Acute Kidney Injury score more comprehensively describes the outcome implications of severe acute kidney injury than traditional staging methods.

Using kinetic eGFR to identify acute kidney injury risk in children undergoing cardiac transplantation.

BACKGROUND: Acute kidney injury (AKI) is common following pediatric cardiac transplantation. Since no treatments exist, strategies focus on early identification and prevention. Kinetic glomerular filtration rate (kGFR) was developed to assess renal function in the non-steady state. Although used to predict AKI in adults, kGFR has not been explored in children. Our study examines AKI and the ability of kGFR to identify AKI risk in pediatric heart transplant recipients. METHODS: One hundred and seventy-five patients under 21 years who underwent cardiac transplantation at Lucile Packard Children's Hospital between September 2007-December 2017 were included. kGFR1 was calculated using pre-operative and immediate post-operative creatinines; kGFR2 was calculated with the first two post-operative creatinines. The primary outcome was AKI as defined by the Kidney Disease: Improving Global Outcomes criteria. RESULTS: One hundred and thirty-one (75%) and 78 (45%) patients developed AKI and severe AKI, respectively; 5 (2.9%) required dialysis. kGFR was moderately associated with post-operative AKI risk. The adjusted area under the curve (AUC) for kGFR1 was 0.72 (discovery) and 0.65 (validation). The AUC for kGFR2 was 0.72 (discovery) and 0.68 (validation). CONCLUSIONS: AKI is pervasive in children undergoing cardiac transplant, particularly in the 24 h after surgery. kGFR moderately identifies AKI risk and may represent a novel risk stratification technique. IMPACT: Our research suggests that kGFR, a dynamic assessment of renal function that uses readily available laboratory values, can moderately identify AKI risk in children undergoing cardiac transplantation. Current published studies on kGFR are in adult populations; this study represents the first formal study of kGFR in a pediatric population. kGFR may serve as an early AKI indicator, allowing providers to implement preventative strategies sooner in a patient's clinical course.

Baseline creatinine determination method impacts association between acute kidney injury and clinical outcomes.

BACKGROUND: Current consensus definition for acute kidney injury (AKI) does not specify how baseline serum creatinine should be determined. We assessed how baseline determination impacted AKI incidence and association between AKI and clinical outcomes. METHODS: We retrospectively applied empirical (measured serum creatinine) and imputed (age/height) baseline estimation methods to pediatric patients discharged between 2014 and 2019 from an academic hospital. Using each method, we estimated AKI incidence and assessed area under ROC curve (AUROC) for AKI as a predictor of three clinical outcomes: application of AKI billing code (proxy for more clinically overt disease), inpatient mortality, and post-hospitalization chronic kidney disease. RESULTS: Incidence was highly variable across baseline methods (12.2-26.7%). Incidence was highest when lowest pre-admission creatinine was used if available and Schwartz bedside equation was used to impute one otherwise. AKI was more predictive of application of an AKI billing code when baseline was imputed universally, regardless of pre-admission values (AUROC 80.7-84.9%) than with any empirical approach (AUROC 64.5-76.6%). AKI was predictive of post-hospitalization CKD when using universal imputation baseline methods (AUROC 67.0-74.6%); AKI was not strongly predictive of post-hospitalization CKD when using empirical baseline methods (AUROC 46.4-58.5%). Baseline determination method did not affect the association between AKI and inpatient mortality. CONCLUSIONS: Method of baseline determination influences AKI incidence and association between AKI and clinical outcomes, illustrating the need for standard criteria. Imputing baseline for all patients, even when preadmission creatinine is available, may identify a more clinically relevant subset of the disease.

Policy in pediatric nephrology: successes, failures, and the impact on disparities.

Pediatric nephrology has a history rooted in pediatric advocacy and has made numerous contributions to child health policy affecting pediatric kidney diseases. Despite this progress, profound social disparities remain for marginalized and socially vulnerable children with kidney disease. Different risk factors, such as genetic predisposition, environmental factors, social risk factors, or health care access influence the emergence and progression of pediatric kidney disease, as well as access to life-saving interventions, leading to disparate outcomes. This review will summarize the breadth of literature on social determinants of health in children with kidney disease worldwide and highlight policy-based initiatives that mitigate the adverse social factors to generate greater equity in pediatric kidney disease.

Acute kidney injury and chronic kidney disease after combined heart-liver transplant in patients with congenital heart disease: A retrospective case series.

Although it is known that children undergoing heart transplantation are at increased risk for both AKI and CKD, renal function following CHLT remains understudied. All pediatric CHLT patients from 2006 to 2019 were included. The prevalence of AKI in the first 7 post-operative days, renal recovery at 30 post-operative days, and CKD were ascertained. AKI was defined as an increase in creatinine greater than 1.5 times baseline, and CKD, as an eCrCl less than 90 mL/min/1.73 m2 . The need for RRT was also analyzed. 10 patients were included, with an average age of 20 years and an average listing time of 130 days. Preoperatively, the median eCrCl was 91.12 mL/min/m2 (IQR 70.51, 127.75 min/mL/m2 ). 5 (50%) patients had CKD, with 4 at stage 2 and 1 at stage 3. AKI occurred post-operatively in 3 of 9 (33%) patients: 2 at stage 1 and 1 at stage 2. 2 (67%) resolved by 7 days. Of the 5 patients who reached their 1-year follow-up, 1 (20%) had stage 3 CKD. Among 2 patients, neither had CKD at 5 years. One patient required RRT 2 weeks after CHLT. Despite an increased prevalence of preoperative CKD, patients undergoing CHLT have a lower AKI prevalence than those receiving an isolated heart or liver transplant. Of those with AKI, early renal recovery is common, although at 1 year CKD remains present in 20%. Among long-term survivors, normal renal function is achievable.

Acute kidney injury in hospitalized children: consequences and outcomes.

Over the past decade, the nephrology and critical care communities have adopted a consensus approach to diagnosing acute kidney injury (AKI) and, as a result, we have seen transformative changes in our understanding of pediatric AKI epidemiology. The data regarding outcomes among neonates and children who develop AKI have become far more robust and AKI has been clearly linked with an increased need for mechanical ventilation, longer inpatient stays, and higher mortality. Though AKI was historically thought to be self-limited, we now know that renal recovery is far from universal, particularly when AKI is severe; the absence of recovery from AKI also carries longitudinal prognostic implications. AKI survivors, especially those without full recovery, are at risk for chronic renal sequelae including proteinuria, hypertension, and chronic kidney disease. This review comprehensively describes AKI-related outcomes across the entire pediatric age spectrum, using the most rigorous studies to identify the independent effects of AKI events.

Nephrotoxins and nephrotoxic acute kidney injury.

Although the concept of nephrotoxicity has been recognized for more than 80 years, interest in nephrotoxins has intensified dramatically over the past two decades. Much of this attention has rightfully been focused on pharmaceutical agents and iatrogenic harm; however, it is important for providers to recognize that nephrotoxins can be found in naturally occurring substances as well. Although nephrotoxins exist in a myriad of forms, the means by which they induce injury can be organized into a few categories. For most of these agents, regardless of the mechanism, the final common pathway is acute kidney injury (AKI). Unfortunately, therapeutic options are limited and no treatments currently exist to reverse nephrotoxic AKI once it occurs. As a result, current strategies focus on increased awareness, nephrotoxin avoidance, early injury detection, and mitigation of disease severity. The goal of this review is to summarize our current understanding of nephrotoxic mechanisms and the epidemiology of nephrotoxic AKI. Additionally, avoidance and preventative strategies are discussed, screening approaches are suggested, and chronic monitoring recommendations are made.

Clinical evaluation of the Prismaflex™ HF 20 set and Prismaflex™ system 7.10 for acute continuous kidney replacement therapy (CKRT) in children.

BACKGROUND: Continuous kidney replacement therapy (CKRT) is a common modality for treatment of severe acute kidney injury (AKI) in children. Adult technologies routinely utilized to provide this therapy have a large extracorporeal volume. The Prismaflex™ HF20 filter set has a relatively low extracorporeal blood volume of 60 mL, which provides technological benefit for smaller children compared with current filter sets available in the USA. METHODS: We conducted a multicenter, open-label single group study to evaluate whether the Prismaflex™ HF20 filter set delivers efficacious and safe CKRT to support patients with AKI, fluid overload, or both in pediatric patients weighing ≥ 8 to 20 kg. RESULTS: Twenty-three patients were enrolled between April 24, 2016 and April 8, 2018. The mean reduction in blood urea nitrogen from baseline to 24 h was 58.12 ± 20.08% (95% CI, - 68.45 and - 47.79 (p = 0.0008)). Median cumulative normalized effluent rate at 24 h was 60.8 mL/kg/h (25.9, 83.7). None of the patients participating in the study suffered a serious adverse event; thus, no obvious safety concerns were noted. CONCLUSIONS: We suggest that the Prismaflex HF20™ filter set used in conjunction with the Prismaflex™ System Software Version 7.10 or 7.20 is a suitable alternative to larger filter sets for use in pediatric patients weighing less than 20 kg. Graphical abstract.

Plasma pseudouridine levels reflect body size in children on hemodialysis.

BACKGROUND: Dialysis in children as well as adults is prescribed to achieve a target spKt/Vurea, where Vurea is the volume of distribution of urea. Waste solute production may however be more closely correlated with body surface area (BSA) than Vurea which rises in proportion with body weight. Plasma levels of waste solutes may thus be higher in smaller patients when targeting spKt/Vurea since they have higher BSA relative to body weight. This study measured levels of pseudouridine (PU), a novel marker solute whose production is closely proportional to BSA, to test whether prescription of dialysis to a target spKt/Vurea results in higher plasma levels of PU in smaller children. METHODS: PU and urea nitrogen (ureaN) were measured in plasma and dialysate at the midweek hemodialysis session in 20 pediatric patients, with BSA ranging from 0.65-1.87m2. Mathematical modeling was employed to estimate solute production rates and average plasma solute levels. RESULTS: The dialytic clearance (Kd) of PU was proportional to that of ureaN (average KdPU/KdUreaN 0.69 ± 0.13, r2 0.84, p < 0.001). Production of PU rose in proportion with BSA (r2 0.57, p < 0.001). The pretreatment plasma level of PU was significantly higher in smaller children (r2 0.20, p = 0.051) while the pretreatment level of ureaN did not vary with size. CONCLUSIONS: Prescribing dialysis based on urea kinetics may leave uremic solutes at higher levels in small children. Measurement of a solute produced proportional to BSA may provide a better index of dialysis adequacy than measurement of urea.

Antimicrobial Disposition During Pediatric Continuous Renal Replacement Therapy Using an Ex Vivo Model.

OBJECTIVES: Little is known on the impact of continuous renal replacement therapy on antimicrobial dose requirements in children. In this study, we evaluated the pharmacokinetics of commonly administered antimicrobials in an ex vivo continuous renal replacement therapy model. DESIGN: An ex vivo continuous renal replacement therapy circuit was used to evaluate drug-circuit interactions and determine the disposition of five commonly used antimicrobials (meropenem, piperacillin, liposomal amphotericin B, caspofungin, and voriconazole). SETTING: University research laboratory. PATIENTS: None. INTERVENTIONS: Antimicrobials were administered into a reservoir containing whole human blood. The reservoir was connected to a pediatric continuous renal replacement therapy circuit programmed for a 10 kg child. Continuous renal replacement therapy was performed in the hemodiafiltration mode and in three phases correlating with three different continuous renal replacement therapy clearance rates: 1) no clearance (0 mL/kg/hr, to measure adsorption), 2) low clearance (20 mL/kg/hr), and 3) high clearance (40 mL/kg/hr). Blood samples were drawn directly from the reservoir at baseline and at 5, 20, 60, and 180 minutes during each phase. Five independent continuous renal replacement therapy runs were performed to assess inter-run variability. Antimicrobial concentrations were measured using validated liquid chromatography-mass spectrometry assays. A closed-loop, flow-through pharmacokinetic model was developed to analyze concentration-time profiles for each drug. MEASUREMENTS AND MAIN RESULTS: Circuit adsorption of antimicrobials ranged between 13% and 27%. Meropenem, piperacillin, and voriconazole were cleared by the continuous renal replacement therapy circuit and clearance increased with increasing continuous renal replacement therapy clearance rates (7.66 mL/min, 4.97 mL/min, and 2.67 mL/min, respectively, for high continuous renal replacement therapy clearance). Amphotericin B and caspofungin had minimal circuit clearance and did not change with increasing continuous renal replacement therapy clearance rates. CONCLUSIONS: Careful consideration of drug-circuit interactions during continuous renal replacement therapy is essential for appropriate drug dosing in critically ill children. Antimicrobials have unique adsorption and clearance profiles during continuous renal replacement therapy, and this knowledge is important to optimize antimicrobial therapy.

Renal injury and recovery in pediatric patients after ventricular assist device implantation and cardiac transplant.

BACKGROUND: The use of ventricular assist devices (VADs) in children with heart failure may be of particular benefit to those with accompanying renal failure, as improved renal function is seen in some, but not all recipients. We hypothesized that persistent renal dysfunction at 7 days and/or 1 month after VAD implantation would predict chronic kidney disease (CKD) 1 year after heart transplantation (HT). METHODS: Linkage analysis of all VAD patients enrolled in both the PEDIMACS and PHTS registries between 2012 and 2016. Persistent acute kidney injury (P-AKI), defined as a serum creatinine ≥1.5× baseline, was assessed at post-implant day 7. Estimated glomerular filtration rate (eGFR) was determined at implant, 30 days thereafter, and 12 months post-HT. Pre-implant eGFR, eGFR normalization (to ≥90 mL/min/1.73 m2 ), and P-AKI were used to predict post-HT CKD (eGFR <90 mL/min/1.73 m2 ). RESULTS: The mean implant eGFR was 85.4 ± 46.5 mL/min/1.73 m2 . P-AKI was present in 19/188 (10%). Mean eGFR at 1 month post-VAD implant was 131.1 ± 62.1 mL/min/1.73 m2 , significantly increased above baseline (P < 0.001). At 1 year post-HT (n = 133), 60 (45%) had CKD. Lower pre-implant eGFR was associated with post-HT CKD (OR 0.99, CI: 0.97-0.99, P = 0.005); P-AKI was not (OR 0.96, CI: 0.3-3.0, P = 0.9). Failure to normalize renal function 30 days after implant was highly associated with CKD at 1 year post-transplant (OR 12.5, CI 2.8-55, P = 0.003). CONCLUSIONS: Renal function improves after VAD implantation. Lower pre-implant eGFR and failure to normalize renal function during the support period are risk factors for CKD development after HT.

Evaluation and management of elevated blood pressures in hospitalized children.

Elevated blood pressures (BP) are common among hospitalized children and, if not recognized and treated promptly, can lead to potentially significant consequences. Even though we have normative BP data and well-developed guidelines for the diagnosis and management of hypertension (HTN) in the ambulatory setting, our understanding of elevated BPs and their relationship to HTN in hospitalized children is limited. Several issues have hampered our ability to diagnose and manage HTN in the inpatient setting including the common presence of physiologic conditions, which are associated with transient BP elevations (i.e., pain or anxiety), non-standard approaches to BP measurement, a lack of clarity regarding appropriate diagnostic and therapeutic thresholds, and marginal outcome data. The purpose of this review is to highlight the issues and challenges surrounding BP monitoring, assessment of elevated BPs, and the diagnosis of HTN in hospitalized children. Extrapolating from currently available clinical practice guidelines and utilizing the best data available, we aim to provide guidelines regarding evaluation and treatment of elevated BP in hospitalized children.

Oliguria and Acute Kidney Injury in Critically Ill Children: Implications for Diagnosis and Outcomes.

OBJECTIVES: Consensus definitions for acute kidney injury are based on changes in serum creatinine and urine output. Although the creatinine criteria have been widely applied, the contribution of the urine output criteria remains poorly understood. We evaluated these criteria individually and collectively to determine their impact on the diagnosis and outcome of severe acute kidney injury. DESIGN AND SETTING: Post hoc analysis of Assessment of Worldwide Acute Kidney Injury, Renal Angina, and Epidemiology study-a prospective international observational multicenter study. PATIENTS: Critically ill children enrolled in Assessment of Worldwide Acute Kidney Injury, Renal Angina and, Epidemiology database. MEASUREMENT: To assess the differential impact of creatinine and urine output criteria on severe acute kidney injury (Kidney Disease: Improving Global Outcomes stage ≥ 2). Patients were divided into four cohorts: no-severe acute kidney injury, severe acute kidney injury by creatinine criteria only, severe acute kidney injury by urine output criteria only, and severe acute kidney injury by both creatinine and urine output criteria. RESULTS: Severe acute kidney injury occurred in 496 of 3,318 children (14.9%); 343 (69.2%) were creatinine criteria only, 90 (18.1%) were urine output criteria only, and 63 (12.7%) were both creatinine and urine output criteria. Twenty-eight-day mortality for creatinine criteria only and urine output criteria only patients was similar (6.7% vs 7.8%) and higher than those without severe acute kidney injury (2.9%; p < 0.01). Both creatinine and urine output criteria patients had higher mortality than creatinine criteria only and urine output criteria only patients (38.1%; p < 0.001). Compared with patients without severe acute kidney injury, the relative risk of receiving dialysis increased from 9.1 (95% CI, 3.9-21.2) in creatinine criteria only, to 28.2 (95% CI, 11.8-67.7) in urine output criteria only, to 165.7 (95% CI, 86.3-318.2) in both creatinine and urine output criteria (p < 0.01). CONCLUSIONS: Nearly one in five critically ill children with acute kidney injury do not experience increase in serum creatinine. These acute kidney injury events, which are only identified by urine output criteria, are associated with comparably poor outcomes as those diagnosed by changes in creatinine. Children meeting both criteria had worse outcomes than those meeting only one. We suggest oliguria represents a risk factor for poorer outcomes among children who develop acute kidney injury. Application of both the creatinine and urine output criteria leads to a more comprehensive epidemiologic assessment of acute kidney injury and identifies a subset of children with acute kidney injury who are at higher risk for morbidity and mortality.