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Normal renal physiology in term neonates provides them with adequate function to maintain proper homeostasis. Premature infants are born with less glomeruli, and the extra-uterine environment is not optimal for renal development, especially in context of acute kidney injury. Premature infants are born with poor ability to clear waste products, and maintain electrolyte/fluid balance, thereby relying on the clinician to provide adequate fluid/electrolyte and nutrition provision to assure homeostasis. Neonatal acute kidney injury is common in premature infants, infants with perinatal depression, neonates who receive cardiopulmonary bypass surgery or require extra-corporeal membrane oxygenation. They are very commonly exposed to nephrotoxic medications. Despite this, neonates represent one of the least studied critically ill population. Recent studies using contemporary AKI definitions elucidate that AKI is very common in the neonatal intensive care unit. Renal replacement therapy can be provided to neonates using peritoneal dialysis, intermittent hemodialysis, and continuous renal replacement therapy. New machines and filters have been developed which promise to decrease the complexity and risks of these therapies.

Objective To determine the association of dysnatremia in the first postnatal week and risk of acute kidney injury (AKI) and mortality. Study design A secondary analysis of 1979 neonates in the AWAKEN cohort evaluated the association of dysnatremia with (1) AKI in the first postnatal week and (2) mortality, utilizing time-varying Cox proportional hazard models. Result Dysnatremia developed in 50.2% of the cohort and was not associated with AKI. Mortality was associated with hyponatremia (HR 2.15, 95% CI 1.07-4.31), hypernatremia (HR 4.23, 95% CI 2.07-8.65), and combined hypo/hypernatremia (HR 6.39, 95% CI 2.01-14.01). In stratified models by AKI-status, hypernatremia and hypo/hypernatremia increased risk of mortality in neonates without AKI. Conclusion Dysnatremia within the first postnatal week was associated with increased risk of mortality. Hypernatremia and combined hypo/hypernatremia remained significantly associated with mortality in neonates without AKI. This may reflect fluid strategies kidney injury independent of creatinine and urine-output defined AKI, and/or systemic inflammation.

ImportanceExtremely low gestational age neonates are at risk of disorders of fluid balance (FB), defined as change in fluid weight over a specific period. Few data exist on the association between FB and respiratory outcomes in this population.ObjectiveTo describe FB patterns and evaluate the association of FB with respiratory outcomes in a cohort of extremely low gestational age neonates.Design, Setting, and ParticipantsThis study is a secondary analysis of the Preterm Erythropoietin Neuroprotection Trial (PENUT), a phase 3 placebo-controlled randomized clinical trial of erythropoietin in extremely premature neonates conducted in 30 neonatal intensive care units in the US from December 1, 2013, to September 31, 2016. This analysis included 874 extremely premature neonates born at 24 to 27 weeks’ gestation who were enrolled in the PENUT study. Secondary analysis was performed in November 2021.ExposuresPrimary exposure was peak FB during the first 14 postnatal days. The FB was calculated as percent change in weight from birth weight (BW) as a surrogate for FB.Main Outcomes and MeasuresThe primary outcome was mechanical ventilation on postnatal day 14. The secondary outcome was a composite of severe bronchopulmonary dysplasia (BPD) or death.ResultsA total of 874 neonates (449 [51.4%] male; mean [SD] BW, 801 [188] g; 187 [21.4%] Hispanic, 676 [77.3%] non-Hispanic, and 11 [1.3%] of unknown ethnicity; 226 [25.9%] Black, 569 [65.1%] White, 51 [5.8%] of other race, and 28 [3.2%] of unknown race) were included in this analysis. Of these 874 neonates, 458 (52.4%) received mechanical ventilation on postnatal day 14, and 291 (33.3%) had severe BPD or had died. Median peak positive FB was 11% (IQR, 4%-20%), occurring on postnatal day 13 (IQR, 9-14). A total of 93 (10.6%) never decreased below their BW. Neonates requiring mechanical ventilation at postnatal day 14 had a higher peak FB compared with those who did not require mechanical ventilation (15% above BW vs 8% above BW, P P P P Conclusions and RelevanceIn this secondary analysis of a randomized clinical trial, peak FB was associated with mechanical ventilation on postnatal day 14 and severe BPD or death. Fluid balance in the first 3 postnatal days and time to return to BW may be potential targets to help guide management and improve respiratory outcomes.Trial RegistrationClinicalTrials.gov Identifier: NCT01378273

ImportanceIncreasing evidence indicates that acute kidney injury (AKI) occurs frequently in children and young adults and is associated with poor short-term and long-term outcomes. Guidance is required to focus efforts related to expansion of pediatric AKI knowledge.ObjectiveTo develop expert-driven pediatric specific recommendations on needed AKI research, education, practice, and advocacy.Evidence ReviewAt the 26th Acute Disease Quality Initiative meeting conducted in November 2021 by 47 multiprofessional international experts in general pediatrics, nephrology, and critical care, the panel focused on 6 areas: (1) epidemiology; (2) diagnostics; (3) fluid overload; (4) kidney support therapies; (5) biology, pharmacology, and nutrition; and (6) education and advocacy. An objective scientific review and distillation of literature through September 2021 was performed of (1) epidemiology, (2) risk assessment and diagnosis, (3) fluid assessment, (4) kidney support and extracorporeal therapies, (5) pathobiology, nutrition, and pharmacology, and (6) education and advocacy. Using an established modified Delphi process based on existing data, workgroups derived consensus statements with recommendations.FindingsThe meeting developed 12 consensus statements and 29 research recommendations. Principal suggestions were to address gaps of knowledge by including data from varying socioeconomic groups, broadening definition of AKI phenotypes, adjudicating fluid balance by disease severity, integrating biopathology of child growth and development, and partnering with families and communities in AKI advocacy.Conclusions and RelevanceExisting evidence across observational study supports further efforts to increase knowledge related to AKI in childhood. Significant gaps of knowledge may be addressed by focused efforts.

Introduction Critically ill children with acute kidney injury (AKI) requiring continuous kidney replacement therapy (CKRT) are at increased risk of death. The selective cytopheretic device (SCD) promotes an immunomodulatory effect when circuit ionized calcium (iCa2+) is maintained at, Graphical abstract

Nephrotoxic medication exposure is a common cause of acute kidney injury (AKI) in hospitalized children. A key component of the NINJA quality improvement initiative is systematic daily serum creatinine assessment in non-critically ill children exposed to ≥ 3 nephrotoxic medications on 1 day, or intravenous aminoglycoside or vancomycin for ≥ 3 days. Daily venipuncture is invasive and associated with disposable and personnel healthcare costs. Urine neutrophil gelatinase-associated lipocalin (uNGAL) is a marker of renal tubular injury associated with certain nephrotoxic medications. We investigated whether uNGAL is a reliable screening tool for AKI in NINJA and could decrease the need for daily venipuncture. This two-center prospective study enrolled 113 children who met NINJA criteria from May 2018 through March 2019. Daily urine samples were obtained for up to the first 7 days of qualifying exposure and 2 days after exposure ended. Our primary outcome was severe AKI (KDIGO stage 2 or 3 AKI). Maximum uNGAL was highest concentration on the day of, or 3 days prior to, severe AKI. The highest uNGAL level from all assessment days was used for patients who did not develop AKI or severe AKI. Urine NGAL thresholds of 150 and 300 ng/ml demonstrated excellent specificity (92.4 and 97.1% respectively) and negative predictive values (93.3 and 92.8% respectively) for ruling out severe AKI. We suggest that uNGAL could be used to supplant some of the daily serum creatinine venipunctures in NINJA. The most optimal combination of serum creatinine and uNGAL assessment requires further study.

Introduction: We aimed to characterize acute kidney injury (AKI), fluid overload (FO), and renal replacement therapy (RRT) utilization by diagnostic categories and examine associations between these complications and mortality by category. Methods: To test our hypotheses, we conducted a retrospective multicenter, cohort study including 446 neonates (categories: 209 with cardiac disease, 114 with congenital diaphragmatic hernia [CDH], 123 with respiratory disease) requiring extracorporeal membrane oxygenation (ECMO) between January 1, 2007, and December 31, 2011. Results: AKI, FO, and RRT each varied by diagnostic category. AKI and RRT receipt were most common in those neonates with cardiac disease. Subjects with CDH had highest peak %FO (51% vs. 28% cardiac vs. 32% respiratory; p < 0.01). Hospital survival was 55% and varied by diagnostic category (45% cardiac vs. 48% CDH vs. 79% respiratory; p < 0.001). A significant interaction suggested risk of mortality differed by diagnostic category in the presence or absence of AKI. In its absence, diagnosis of CDH (vs. respiratory disease) (OR 3.04, 95% CL 1.14–8.11) independently predicted mortality. In all categories, peak %FO (OR 1.20, 95% CL 1.11–1.30) and RRT receipt (OR 2.12, 95% CL 1.20–3.73) were independently associated with mortality. Discussion/Conclusions: Physiologically distinct ECMO diagnoses warrant individualized treatment strategies given variable incidence and effects of AKI, FO, and RRT by category on mortality.

Acute kidney injury (AKI) is common and is associated with poor clinical outcomes in premature neonates. Urine biomarkers hold the promise to improve our understanding and care of patients with kidney disease. Because kidney maturation and gender can impact urine biomarker values in extremely low gestational age neonates (ELGANs), careful control of gestational age (GA) and time is critical to any urine biomarker studies in neonates.To improve our understanding of the potential use of urine biomarkers to detect AKI during the first postnatal weeks, we performed a nested case-control study to evaluate 21 candidate urine AKI biomarkers. Cases include 20 ELGANs with severe AKI. Each case was matched with 2 controls for the same GA week (rounded down to the nearest week), gender, and birth weight (BW) (± 50 g).Urine cystatin C, creatinine, ghrelin, fibroblast growth factor-23 (FGF23), tissue metalloproteinase 2 (TIMP2) and vascular endothelial growth factor A (VEGFa) concentrations were higher in ELGANs with early severe AKI compared to matched control subjects without AKI. Urine epidermal growth factor (EGF) and uromodulin (UMOD) concentrations are lower in cases than controls. Interleukin (IL)-15 was lower on day 1, but higher on day 8 in cases than controls; while VEGFa was lower on day 1, but higher on day 5 in cases than controls.Urine biomarkers hold the promise to improve our ability to reliably detect kidney injury. Interventional studies are needed to determine the biomarkers' ability to predict outcomes, enhance AKI phenotypes, and improve timely interventions which can prevent the sequalae of AKI in ELGANs. A higher resolution version of the Graphical abstract is available as Supplementary information.

With the adoption of standardized neonatal acute kidney injury (AKI) definitions over the past decade and the concomitant surge in research studies, the epidemiology of and risk factors for neonatal AKI have become much better understood. Thus, there is now a need to focus on strategies designed to improve AKI care processes with the goal of reducing the morbidity and mortality associated with neonatal AKI. The 22nd Acute Dialysis/Disease Quality Improvement (ADQI) report provides a framework for such quality improvement in adults at risk for AKI and its sequelae. While many of the concepts can be translated to neonates, there are a number of specific nuances which differ in neonatal AKI care. A group of experts in pediatric nephrology and neonatology came together to provide neonatal-specific responses to each of the 22nd ADQI consensus statements.

BACKGROUND: To determine the prevalence and severity of acute kidney injury (AKI) at different time frames in relation to gestational age (GA) and birthweight (BW) in extremely low gestational age neonates (ELGAN). Our hypothesis is that ELGAN with lower GA and lower BW have higher AKI rates. METHODS: 923 ELGAN enrolled in the Preterm Erythropoietin Neuroprotection Trial were evaluated from birth until death or hospital discharge. AKI was defined according to kidney disease: improving global outcomes (KDIGO) definition from clinically-derived serum creatinine (SCr) measurements. Severe AKI was defined as stage 2 or higher. RESULTS: For the entire cohort, 351/923 (38.0%, CI = 34.8–41.3%) had at least one episode of stage 1 or higher AKI and 168/923 (18.2%, CI = 15.7–20.7%) had at least one episode of severe (stage 2 or higher) AKI. The prevalence of AKI stage 1 or higher for the entire cohort during the early (days 3–7), middle (days 8–14) and late follow-up period (after day 14) was 112/923 (12.1%, CI = 10.0–14.3%), 142/891 (15.9%, CI = 13.5–18.4%) and 249/875 (28.5%, CI = 25.4–31.5%), respectively. The rates of severe AKI during the hospital course were 27.8%, 21.9%, 13.6%, and 9.4% for the 24, 25, 26 and 27 week GA groups respectively. AKI rates were significantly higher with decreasing GA and decreasing BW for stated time trends (all p < 0.01 using tests for trend). CONCLUSIONS: AKI is relatively common in ELGAN during their initial hospital course, and is associated with lower GA and BW.

Objective This study aimed to evaluate the association between acute kidney injury (AKI) and bronchopulmonary dysplasia (BPD) in infants born Study Design Present study is a secondary analysis of premature infants born at Results Moderate or severe BPD occurred in 214 of 546 (39%) infants, while death occurred in 32 of 546 (6%); the composite of moderate or severe BPD/death occurred in 246 of 546 (45%). For infants born ≤29 weeks of gestation, the adjusted odds ratio (OR) of AKI and the primary outcome was 1.15 (95% confidence interval [CI] = 0.47–2.86; p = 0.76). Infants born between 29 and 32 weeks of gestation with AKI had four-fold higher odds of moderate or severe BPD/death that remained after controlling for multiple factors (adjusted OR = 4.21, 95% CI: 2.07–8.61; p Conclusion Neonates born between 29 and 32 weeks who develop AKI had a higher likelihood of moderate or severe BPD/death than those without AKI. Further studies are needed to validate our findings and evaluate mechanisms of multiorgan injury.

Objective This study aimed to evaluate the association between acute kidney injury (AKI) and lung outcomes in infants born ≥32 weeks of gestational age (GA). Study Design Secondary analysis of infants ≥32 weeks of GA in the assessment of worldwide acute kidney injury epidemiology in neonates (AWAKEN) retrospective cohort (n = 1,348). We used logistic regression to assess association between AKI and a composite outcome of chronic lung disease (CLD) or death at 28 days of age and linear regression to evaluate association between AKI and duration of respiratory support. Results CLD occurred in 82/1,348 (6.1%) infants, while death occurred in 22/1,348 (1.6%); the composite of CLD/death occurred in 104/1,348 (7.7%). Infants with AKI had an almost five-fold increased odds of CLD/death, which remained after controlling for GA, maternal polyhydramnios, multiple gestations, 5-minute Apgar's score, intubation, and hypoxic–ischemic encephalopathy (adjusted odds ratio [OR] = 4.9, 95% confidence interval [CI]: 3.2–7.4; p Conclusion AKI is associated with CLD/death and longer duration of respiratory support in infants born at ≥32 weeks of GA. Further prospective studies are needed to elucidate the pathophysiologic relationship.

Acute kidney injury (AKI) and fluid overload (FO) are common complications of extracorporeal membrane oxygenation (ECMO). The purpose of this study was to characterize AKI and FO in children receiving extracorporeal cardiopulmonary resuscitation (eCPR). We performed a multicenter retrospective study of children who received eCPR. AKI was assessed during ECMO and FO defined as

In this state-of-the-art review, we highlight the major advances over the last 5 years in neonatal acute kidney injury (AKI). Large multicenter studies reveal that neonatal AKI is common and independently associated with increased morbidity and mortality. The natural course of neonatal AKI, along with the risk factors, mitigation strategies, and the role of AKI on short- and long-term outcomes, is becoming clearer. Specific progress has been made in identifying potential preventive strategies for AKI, such as the use of caffeine in premature neonates, theophylline in neonates with hypoxic-ischemic encephalopathy, and nephrotoxic medication monitoring programs. New evidence highlights the importance of the kidney in “crosstalk” between other organs and how AKI likely plays a critical role in other organ development and injury, such as intraventricular hemorrhage and lung disease. New technology has resulted in advancement in prevention and improvements in the current management in neonates with severe AKI. With specific continuous renal replacement therapy machines designed for neonates, this therapy is now available and is being used with increasing frequency in NICUs. Moving forward, biomarkers, such as urinary neutrophil gelatinase–associated lipocalin, and other new technologies, such as monitoring of renal tissue oxygenation and nephron counting, will likely play an increased role in identification of AKI and those most vulnerable for chronic kidney disease. Future research needs to be focused on determining the optimal follow-up strategy for neonates with a history of AKI to detect chronic kidney disease.

BACKGROUND Infectious etiologies cause a large portion of pediatric rhabdomyolysis. Among pediatric patients with rhabdomyolysis, it is unknown who will develop acute kidney injury (AKI). We sought to test the hypothesis that a viral etiology would be associated with less AKI in children admitted with rhabdomyolysis than a nonviral etiology. METHODS In this single-center retrospective cohort study, patients RESULTS In total, 319 pediatric patients with rhabdomyolysis were studied. The median age was 13 years. Patients were predominately male (69.9%), non-Hispanic Black (55.2%), and publicly insured (45.1%). We found no difference in the rates of AKI in those with a viral diagnosis versus those without a viral diagnosis (30 of 77 [39.0%] vs 111 of 234 [47.4%]; P = .19). Multivariable analysis revealed that viral diagnosis was not associated with the development of AKI. Patients ≥13 years of age, male patients, and those with proteinuria and elevated serum urea nitrogen on admission had increased odds of developing AKI. CONCLUSIONS In our study, viral rhabdomyolysis did not have lower rates of AKI compared with nonviral etiologies of AKI; therefore, providers should consider continued caution in these patients.

Kidney dysfunction and acute kidney injury (AKI) frequently accompanies neonatal encephalopathy and contributes to neonatal morbidity and mortality. While there are currently no proven therapies for the treatment of AKI, understanding the pathophysiology along with early recognition and treatment of alterations in fluid, electrolyte and metabolic homeostasis that accompany AKI offer opportunity to reduce associated morbidity. Promising new tests and technologies, including urine and serum biomarkers and renal near-infrared spectroscopy offer opportunities to improve diagnosis and monitoring of neonates at risk for kidney injury. Furthermore, recent advances in neonatal kidney supportive therapies such as hemofiltration and hemodialysis may further improve outcomes in this population. This chapter provides an overview of disorders of fluid balance, electrolyte homeostasis and kidney function associated with neonatal encephalopathy and therapeutic hypothermia. Recommendations for fluid and electrolyte management based upon published literature and authors' opinions are provided.

Fluid overload (FO) and acute kidney injury (AKI) occur commonly in children supported with extracorporeal membrane oxygenation (ECMO). Continuous renal replacement therapy (CRRT) may be used to manage AKI and FO in children on ECMO. In 2012, our group surveyed ECMO centers to begin to understand the practice patterns around CRRT and ECMO. Since then, more centers are initiating ECMO for increasingly diverse indications and an increased volume of research quantifies the detrimental impacts of AKI and FO. We, therefore, investigated practice patterns of CRRT utilization during ECMO in children. A multi-point survey instrument was distributed to 116 international neonatal and pediatric ECMO centers. Sixty of 116 (51.7%) international neonatal and pediatric ECMO centers responded. All reports using CRRT on ECMO, compared with 75% from the 2012 survey. Eighty-five percent use CRRT to treat or prevent FO, an increased from 59%. The modality of CRRT therapy differed between in-line (slow continuous ultrafiltration, 84.4%) and machine-based (continuous venovenous hemodiafiltration, 87.3%) methods. Most (65%) do not have protocols for fluid management, AKI, or CRRT on ECMO. Trialing off CRRT is dictated by physician preference in 90% (54/60), with varying definitions of success. In this survey study, we found that CRRT use during pediatric ECMO has increased since 2012 with fluid management representing the predominant indication for initiation. Despite the expanded utilization of CRRT with ECMO, there remains significant practice variation in terms of method, modality, indication, the timing of initiation, fluid management, and discontinuation.

The use of kidney support therapy (KST) for use in managing patients with acute kidney injury (AKI) has expanded greatly in the last several decades. The growing use of KST modalities in children, and now in neonates, has been associated with opportunities for education, clinical research, clinical practice improvements, and outcomes research. A multitude of controversies exist in the field of pediatric KST-many of which are shared by adult critical care nephrology practice. Simultaneously, pediatric KST has led the way to a burgeoning exploration of the importance of fluid overload as it relates to KST initiation and management and also with quality improvement. In this review, we will explore and describe the paradigms contained with pediatric KST used to support children with AKI. In addition to the governing principles related to the mechanics of KST, we will describe the novel aspects of newer support machines and ethical considerations of KST provision. Anticoagulation, dose, and modality will be discussed as well as priming procedures for special considerations. The utilization of KST across pediatric populations represents the next frontier of critical care nephrology.

BACKGROUND AND OBJECTIVES: Provision of kidney replacement therapy (KRT) to manage kidney injury and volume overload in critically ill neonates and small children is technically challenging. The use of machines designed for adult-sized patients, necessitates large catheters, a high extracorporeal volume relative to patient size, and need for blood priming. The Aquadex FlexFlow System (CHF Solutions Inc., Eden Prairie, MN) is an ultrafiltration device designed for fluid removal in adults with diuretic resistant heart failure. It has an extracorporeal volume of 33 ml, which can potentially mitigate some complications seen at onset of KRT in smaller infants. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this multicenter, retrospective case series of children who received KRT with an ultrafiltration device (n=119 admissions, 884 circuits), we report demographics, circuit characteristics, complications, and short- and long-term outcomes. Patients were grouped according to weight (20 kg), and received one of three modalities: slow continuous ultrafiltration, continuous venovenous hemofiltration (CVVH), or prolonged intermittent KRT. Our primary outcome was survival to end of KRT. RESULTS: Treatment patterns and outcomes varied between the groups. In patients who weighed 20 kg, volume overload was the primary indication in 91% and slow continuous ultrafiltration was the most common modality. Patients 20 kg (60% versus 97%), more volume overload at onset, and received KRT for a longer duration. Cardiovascular complications at initiation were seen in 3% of treatments and none were severe. Complications during therapy were seen in 15% treatments and most were vascular access–related. CONCLUSIONS: We report the first pediatric experience using an ultrafiltration device to provide a range of therapies, including CVVH, prolonged intermittent KRT, and slow continuous ultrafiltration. We were able to initiate KRT with minimal complications, particularly in critically ill neonates. There is an unmet need for devices specifically designed for younger patients. Having size-appropriate machines will improve the care of smaller children who require kidney support.

Background: Neonates with serum creatinine (SCr) rise ≥ 0.3 mg/dL and/or 50% SCr rise are more likely to die, even when controlling for confounders. These thresholds have not been tested in newborns. We hypothesized that different gestational age (GA) groups require different SCr thresholds. Methods: Neonates in Assessment of Worldwide Acute Kidney Epidemiology in Neonates (AWAKEN) with ≥1 SCr on postnatal days 1–2 and ≥1 SCr on postnatal days 3–8 were assessed. We compared the mortality predictability of SCr absolute (≥0.3 mg/dL) vs percent (≥50%) rise. Next, we determine usefulness of combining absolute with percent rise. Finally, we determined the optimal absolute, percent, and maximum SCr thresholds that provide the highest mortality area under curve (AUC) and specificity for different GA groups. Results: The ≥0.3 mg/dL rise outperformed ≥50% SCr rise. Addition of percent rise did not improve mortality predictability. The optimal SCr thresholds to predict AUC and specificity were ≥0.3 & ≥0.6 mg/dL for ≤29 weeks GA, and ≥0.1 & ≥0.3 mg/dL for >29 week GA. The maximum SCr value provides great specificity. Conclusion: Unique SCr rise cutoffs for different GA improves outcome prediction. Percent SCr rise does not add value to the neonatal AKI definition.

BACKGROUND: Most studies of neonatal acute kidney injury (AKI) have focused on the first week following birth. Here, we determined the outcomes and risk factors for late AKI (>7d). METHODS: The international AWAKEN study examined AKI in neonates admitted to an intensive care unit. Late AKI was defined as occurring >7 days after birth according to the KDIGO criteria. Models were constructed to assess the association between late AKI and death or length of stay. Unadjusted and adjusted odds for late AKI were calculated for each perinatal factor. RESULTS: Late AKI occured in 202/2152 (9%) of enrolled neonates. After adjustment, infants with late AKI had higher odds of death (aOR:2.1, p=0.02) and longer length of stay (parameter estimate:21.9, p

IMPORTANCE: Many children with return of spontaneous circulation (ROSC) following cardiac arrest (CA) experience acute kidney injury (AKI). The impact of therapeutic hypothermia on the epidemiology of post-CA AKI in children has not been fully investigated. OBJECTIVE: The study aims were to: 1) describe the prevalence of severe AKI in comatose children following out-of-hospital CA (OHCA), 2) identify risk factors for severe AKI, 3) evaluate the impact of therapeutic hypothermia on the prevalence of severe AKI, and 4) evaluate the association of severe AKI with survival and functional outcomes. DESIGN: A post hoc secondary analysis of data from the Therapeutic Hypothermia after Pediatric Cardiac Arrest Out-of-Hospital (THAPCA-OH) trial. SETTING: Thirty-six pediatric intensive care units in the United States and Canada. PARTICIPANTS: Of 282 eligible subjects with an initial creatinine obtained within 24 hours of randomization, 148 were randomized to therapeutic hypothermia and 134 were randomized to therapeutic normothermia. MAIN OUTCOMES AND MEASURES: Primary outcome was prevalence of severe AKI, as defined by stage 2 and 3 Kidney Disease Improving Global Outcomes (KDIGO) consensus definition; secondary outcome was survival with a favorable neurobehavioral outcome. For this study, risk factors and outcomes were compared between those with/without severe AKI. RESULTS: Of the 282 subjects enrolled, 180 (64%) developed AKI of which 117 (41% of all enrolled) developed severe AKI. Multivariable modeling found younger age, longer duration of chest compressions, higher lactate level at time of temperature intervention and higher number of vasoactive agents through day 1 of intervention associated with severe AKI. There was no difference in severe AKI between therapeutic hypothermia (39.9%) and therapeutic normothermia (43.3%) groups (p=0.629). Survival was lower in those with severe AKI at 28 days (21% vs no severe AKI 49%, p

BACKGROUND Our understanding of the normative concentrations of urine biomarkers in premature neonates is limited. METHODS We evaluated urine from 750 extremely low gestational age (GA) neonates without severe acute kidney injury (AKI) to determine how GA affects ten different urine biomarkers at birth and over the first 30 postnatal days. Then, we investigated if the urine biomarkers changed over time at 27, 30, and 34 weeks postmenstrual age (PMA). Next, we evaluated the impact of sex on urine biomarker concentrations at birth and over time. Finally, we evaluated if urine biomarkers were impacted by treatment with erythropoietin (Epo). RESULTS We found that all ten biomarker concentrations differ at birth by GA and that some urine biomarker concentrations increase, while others decrease over time. At 27 weeks PMA, 7/10 urine biomarkers differed by GA. By 30 weeks PMA, 5/10 differed, and by 34 weeks PMA, only osteopontin differed by GA. About half of the biomarker concentrations differed by sex, and 4/10 showed different rates of change over time between males vs. females. We found no differences in urine biomarkers by treatment group. CONCLUSIONS The temporal patterns, GA, and sex differences need to be considered in urine AKI biomarker analyses. IMPACT Urine biomarker concentrations differ by GA at birth. Some urine biomarkers increase, while others decrease, over the first 30 postnatal days. Most urine biomarkers differ by GA at 27 weeks PMA, but are similar by 34 weeks PMA. Some urine biomarkers vary by sex in premature neonates. Urine biomarkers did not differ between neonates randomized to placebo vs. Epo.

Aim Determine 1) frequency and risk factors for acute kidney injury (AKI) after in-hospital cardiac arrest (IHCA) in the Therapeutic Hypothermia after Pediatric Cardiac Arrest In-Hospital (THAPCA-IH) trial and associated outcomes; 2) impact of temperature management on post-IHCA AKI. Methods Secondary analysis of THAPCA-IH; a randomized controlled multi-national trial at 37 children’s hospitals. Eligibility Serum creatinine (Cr) within 24 h of randomization. Outcomes Prevalence of severe AKI defined by Stage 2 or 3 Kidney Disease Improving Global Outcomes Cr criteria. 12-month survival with favorable neurobehavioral outcome. Analyses stratified by entire cohort and cardiac subgroup. Risk factors and outcomes compared among cohorts with and without severe AKI. Results Subject randomization: 159 to hypothermia, 154 to normothermia. Overall, 80% (249) developed AKI (any stage), and 66% (207) developed severe AKI. Cardiac patients (204, 65%) were more likely to develop severe AKI (72% vs 56%,p = 0.006). Preexisting cardiac or renal conditions, baseline lactate, vasoactive support, and systolic blood pressure were associated with severe AKI. Comparing hypothermia versus normothermia, there were no differences in severe AKI rate (63% vs 70%,p = 0.23), peak Cr, time to peak Cr, or freedom from mortality or severe AKI (p = 0.14). Severe AKI was associated with decreased hospital survival (48% vs 65%,p = 0.006) and decreased 12-month survival with favorable neurobehavioral outcome (30% vs 53%,p Conclusion Severe post-IHCA AKI occurred frequently especially in those with preexisting cardiac or renal conditions and peri-arrest hemodynamic instability. Severe AKI was associated with decreased survival with favorable neurobehavioral outcome. Hypothermia did not decrease incidence of severe AKI post-IHCA.

Background/Purpose Continuous renal replacement therapy (CRRT) is difficult in neonates for several reasons, including problems with catheter placement and maintenance. We sought to compare outcomes between standard hemodialysis catheters (HDC) and 6Fr-tunneled central venous catheters (TC-6Fr). Methods We evaluated neonates who received CRRT from December 2013 – January 2018. All patients received CRRT with the Aquadex (Baxter Corporation, Minneapolis, Minnesota) circuit. Data regarding patient demographics, CRRT indication, catheter days, reason for removal, and catheter-specific complications were analyzed. Results Forty-six catheters were placed in 26 neonates; nine of these were 6Fr-tunneled catheters. The median age and mean weight at CRRT initiation was 9.5 days (IQR 4–31) and 3.5 kg (+/- 0.6 kg), respectively. TC-6Fr lasted longer (median of 28 days vs 10 days, p = 0.02), required fewer revisions (0 vs 0.16/10 catheter days) and were less commonly removed due to bleeding complications (0% vs 10.8%), occlusion (11.1% vs 18.9%), or malposition (0% vs 8.1%); none of these differences were statistically significant. TC-6Fr were associated with higher infection rates (33.3% vs 0%, p = 0.01) than HDC. Conclusions TC-6Fr use resulted in less need for catheter revisions and provided longer-lasting vascular access, which may influence infection rates. This catheter provides neonates in need of CRRT more reliable vascular access. Level of evidence : III.

BACKGROUND AND OBJECTIVES: AKI is associated with poor short- and long-term outcomes. Questions remain about the frequency and timing of AKI, and whether AKI is a cause of death in extremely low gestational age neonates. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The Recombinant Erythropoietin for Protection of Infant Kidney Disease Study examines the kidney outcomes of extremely low gestational age neonates enrolled in the Preterm Epo Neuroprotection study, a randomized, placebo-controlled trial of recombinant human erythropoietin. We included 900 of 941 patients enrolled in Preterm Epo Neuroprotection. Baseline characteristics were compared by primary exposure (severe AKI versus none/stage 1 AKI) using unadjusted logistic regression models. Cox regression models estimated the relationship between severe AKI and death after adjustment for potential confounders. Time-dependent AKI was modeled as a binary outcome and a categorical variable by stage of AKI. We fit Cox models using time-dependent AKI status lagged by

Nephrotoxic medication exposure is a common cause of acute kidney injury (AKI) in hospitalized children. A key component of the NINJA quality improvement initiative is systematic daily serum creatinine assessment in non-critically ill children exposed to ≥ 3 nephrotoxic medications on 1 day, or intravenous aminoglycoside or vancomycin for ≥ 3 days. Daily venipuncture is invasive and associated with disposable and personnel healthcare costs. Urine neutrophil gelatinase-associated lipocalin (uNGAL) is a marker of renal tubular injury associated with certain nephrotoxic medications. We investigated whether uNGAL is a reliable screening tool for AKI in NINJA and could decrease the need for daily venipuncture.This two-center prospective study enrolled 113 children who met NINJA criteria from May 2018 through March 2019. Daily urine samples were obtained for up to the first 7 days of qualifying exposure and 2 days after exposure ended. Our primary outcome was severe AKI (KDIGO stage 2 or 3 AKI). Maximum uNGAL was highest concentration on the day of, or 3 days prior to, severe AKI. The highest uNGAL level from all assessment days was used for patients who did not develop AKI or severe AKI.Urine NGAL thresholds of 150 and 300 ng/ml demonstrated excellent specificity (92.4 and 97.1% respectively) and negative predictive values (93.3 and 92.8% respectively) for ruling out severe AKI.We suggest that uNGAL could be used to supplant some of the daily serum creatinine venipunctures in NINJA. The most optimal combination of serum creatinine and uNGAL assessment requires further study.

To study the risk factors and outcomes of severe acute kidney injury (AKI) in neonates with necrotizing enterocolitis.Retrospective chart review of 202 neonates with necrotizing enterocolitis (NEC) (Bell stageIIa) from 2013 to 2018. AKI was defined as per-modified neonatal Kidney Disease: Improving Global Outcomes criteria. Demographic, clinical, and outcome data were compared between neonates without severe AKI (stage 0 and 1 AKI) and those with severe AKI (stage 2 and 3 AKI).Severe AKI occurred in 66/202 (32.6%) of neonates after NEC diagnosis and after 61/104 (58.7%) of surgical NEC diagnoses. On adjusted model, surgical NEC [adjusted odds ratio (aOR) = 30.6; 95% confidence interval (CI) = 8.9, 130.6], outborn [aOR = 3.9; 95% CI = 1.54, 11.0], exposure to antenatal steroids [aOR = 3.0; 95% CI = 1.1, 8.9], and positive blood culture sepsis [aOR = 3.5; 95% CI = 1.3, 10.0] had increased odds for severe AKI. Those with severe AKI required longer hospitalization [124 days (interquartile range (IQR) 88-187) vs. 82 days (IQR 42-126), p 0.001].Severe AKI is common in neonates with NEC who require surgical intervention, are outborn, have positive blood culture sepsis, and receive antenatal steroids. Severe AKI is associated with a significantly longer length of hospitalization.Neonates with NEC, who are transferred from outside hospitals, require surgical NEC management, and/or have a positive blood culture at NEC onset are at the highest odds for severe (stages 2 and 3) AKI. Assessment of urine output is important for patients with NEC. Without it, 11% of those with severe AKI would have been misdiagnosed using serum creatinine alone. Kidney-protective strategies in the pre-, peri-, and postoperative period may improve the morbidity and mortality associated with severe AKI in neonates with NEC.

OBJECTIVE: To evaluate whether extremely low gestational age neonates (ELGANs) randomized to erythropoietin have better or worse kidney-related outcomes during hospitalization and at 22–26 months corrected gestational age (cGA) compared with those randomized to placebo. STUDY DESIGN: We performed an ancillary study to a multicenter double-blind, placebo-controlled randomized clinical trial of erythropoietin in ELGANs. RESULTS: The prevalence of severe (stage 2 or 3) acute kidney injury (AKI) was 18.2%. We did not find a statistically significant difference between those randomized to erythropoietin vs. placebo for in-hospital primary (severe AKI) or secondary outcomes (any AKI and serum creatinine [SCr]/ cystatin C values at days 0, 7, 9 and 14). At 22–26 months cGA, 16% of the cohort had an estimated glomerular filtration rate (eGFR) 30 mg/g, 23% had a systolic blood pressure (SBP) >95(th) percentile for age, and 40% had a diastolic blood pressure (DBP) >95(th) percentile for age. SBP >90(th) percentile occurred less often among recipients of erythropoietin (p95(th) percentile or DBP >90(th) or >95(th) percentiles. CONCLUSIONS: ELGANs have high rates of in-hospital AKI and kidney-related problems at 22–26 months cGA. Recombinant erythropoietin (rhEpo) may protect ELGANs against long-term elevated SBP, but does not appear to protect from AKI, low eGFR, albuminuria or elevated DBP at 22–26 months cGA.

Background: Premature birth is associated with decreased nephron number and an increased risk for chronic kidney disease (CKD). To inform the development of guidelines for kidney follow up of children born prematurely, we undertook a study of individuals born extremely preterm, with the aim of characterizing the prevalence and predictors of microalbuminuria, elevated blood pressure, and/or abnormal kidney volume in adolescence.Methods: Study participants (n = 42) were born before 28 weeks of gestation and were enrolled at birth in the Extremely Low Gestational Age Newborns (ELGAN) study. When participants were 15 years old, we obtained 2 manual blood pressures, a spot urine microalbumin measurement, and sonographic measurements of kidney length and volume.Results: Of the 42 participants, 60% were male, 52% were Caucasian (18% Hispanic), and 43% were African-American. Their median age was 15 (IQR 15, 15.3) years. In 33.3% of the cohort, blood pressure was elevated (>120/80 mmHg). Microalbuminuria (>30 mg/g) was present in 11.9% of the cohort, and kidney volume below the 10th percentile of normative data was present in 14%. Twenty-one (50%) of the sample had at least one kidney abnormality (microalbuminuria, elevated blood pressures, and/or kidney hypoplasia); these individuals were more likely to have experienced neonatal hypotension [55% vs. 17% among those with no kidney abnormality, p = 0.02].Conclusions: Half of adolescents in this subset of ELGAN cohort have at least one risk factor of kidney disease (reduced kidney volume, microalbuminuria, and/or elevated blood pressures) at 15 years of age. This study suggests the importance of monitoring kidney outcomes in children after extremely preterm birth, especially those with a history of neonatal hypotension.

BACKGROUND: To determine whether serum transaminases at presentation predict the need for dialysis in children with hemolytic uremic syndrome (HUS). METHODS: Single-center, retrospective chart review of pediatric patients with HUS. Data collected included demographics, clinical and laboratory parameters, and need for dialysis. These factors were compared between two groups: “dialysis” versus “no dialysis.” Continuous data were compared using a t test whereas categoric data were compared by the chi-squared test. Multivariate logistic regression was performed on a prior set of variables to determine if serum transaminases independently predict the need for dialysis. RESULTS: A total of 70 children were included in the study, of which, 39 (27%) received dialysis. The no-dialysis group had a higher proportion of white patients compared with the dialysis group (74% dialysis versus 94% no dialysis). The only clinical sign at admission associated with dialysis was reduced urine output (56% versus 16%, P

OBJECTIVE: The aim of this study was to characterize continuous renal replacement therapy (CRRT) utilization on extracorporeal membrane oxygenation (ECMO) and to determine the association of both fluid overload (FO) at CRRT initiation and fluid removal during CRRT with mortality in a large multicenter cohort. METHODS: Retrospective chart review of all children < 18 years of age concurrently treated with ECMO and CRRT from January 1, 2007 to December 31, 2011 at 6 tertiary care children’s hospital. Children treated with hemodialysis or peritoneal dialysis were excluded from the FO analysis. MEASUREMENTS AND MAIN RESULTS: A total of 756 of the 1009 children supported with ECMO during the study period had complete FO data. Of these, 357 (47.2%) received either CRRT or were treated with an in-line filter and thus entered into the final analysis. Survival to ECMO decannulation was 66.4% and survival to hospital discharge was 44.3%. CRRT initiation occurred at median of 1 day (IQR 0, 2) after ECMO initiation. Median FO at CRRT initiation was 20.1% (IQR 5, 40) and was significantly lower in ECMO survivors vs. non-survivors (15.3% vs. 30.5% p= 0.005) and in hospital survivors vs. non-survivors (13.5% vs. 25.9%, p= 0.004). Median FO at CRRT discontinuation was significantly lower in ECMO survivors (23% vs. 37.6% p= 0.002) and hospital survivors vs. non-survivors (22.6% vs. 36.1%, p=0.002). In ECMO survivors, after adjusting for pH at CRRT initiation, non-renal complications, ECMO mode, support type, center, patient age and AKI, FO at CRRT initiation (p = 0.01), and FO at CRRT discontinuation (p = 0.0002) were independently associated with duration of ECMO. In a similar multivariable analysis, FO at CRRT initiation (adjusted adds ratio [aOR] 1.09, 95% CI 1.00–1.18, p=0.045) and at CRRT discontinuation (aOR 1.11, 95% CI 1.03–1.19, p=0.01) were independently associated with hospital mortality. CONCLUSIONS: In a multicenter pediatric ECMO cohort, this study demonstrates that severe FO was very common at CRRT initiation. We found an independent association between the degree of FO at CRRT initiation with adverse outcomes including mortality and increased duration of ECMO support. The results suggest intervening prior to the development of significant FO may be a clinical therapeutic target and warrants further evaluation.

Acute kidney injury (AKI) is a common and life-threatening complication in critically ill neonates. Gestational risk factors for AKI include premature birth, intrauterine growth restriction and low birthweight, which are associated with poor nephron development and are often the consequence of pre-gestational and gestational factors, such as poor nutritional status. Our understanding of how to best optimize renal development and prevent AKI is in its infancy; however, the identification of pre-gestational and gestational factors that increase the risk of adverse neonatal outcomes and the implementation of interventions, such as improving nutritional status early in pregnancy, have the potential to optimize fetal growth and reduce the risk of preterm birth, thereby improving kidney health. The overall risk of AKI among critically ill and premature neonates is exacerbated postnatally as these infants are often exposed to dehydration, septic shock and potentially nephrotoxic medications. Strategies to improve outcomes — for example, through careful evaluation of nephrotoxic drugs — may reduce the incidence of AKI and its consequences among this population. Management strategies and updated technology that will support neonates with AKI are greatly needed. Extremely premature infants and those who survive an episode of AKI should be screened for chronic kidney disease until early adulthood. Here, we provide an overview of our current understanding of neonatal AKI, focusing on its relationship to preterm birth and growth restriction. We describe factors that prevent optimal nephrogenesis during pregnancy and provide a framework for future explorations designed to maximize outcomes in this vulnerable population. Acute kidney injury (AKI) is a life-threatening complication in critically-ill neonates. This Review explores the evidence that intrauterine growth restriction, premature birth and low birth weight contribute to neonatal AKI, and discusses perinatal and postnatal risk factors that enhance the risk of AKI among neonates.

In neonates, the validation of urinary biomarkers to diagnose acute kidney injury is a rapidly evolving field. The neonatal population poses unique challenges when assessing the collection, storage, and processing of urinary samples for biomarker analysis. Given this, establishing optimal and consistent sample processing in this population for meaningful use in ongoing clinical trials is important. Urine from a cohort of 19 hospitalized neonatal intensive care unit patients enrolled in the Preterm Erythropoietin Neuroprotection Trial (Clinical Trial NCT01378273) was collected for biomarker analysis by indirect techniques using Fisher-brand cotton balls placed in the diapers. Fourteen urinary biomarkers were measured using commercially available kits via electrochemiluminescence on multiarray plates and compared between paired samples processed with centrifugation prior to storage versus prior to analysis. None of the biomarker concentrations differed between samples undergoing centrifugation prior to storage versus prior to analysis. The difference between samples was within 2% of the estimated concentration for the protein in 12 of 14 biomarkers (86%), and all paired biomarker concentrations were within 4%. The percentage error analysis did not show a difference between paired samples, with biomarker percentage errors smaller than the stated immunoassay coefficient of variance. The urinary concentrations of biomarkers were comparable between paired samples, demonstrating that indirectly collected neonatal urine samples do not require centrifugation after collection and before storage. The ability to use routine urine collection and storage methods to obtain samples for subsequent quantitative immunoassay analysis should facilitate studies of newborns and young children.

Acute kidney injury (AKI) is an under-recognized morbidity of neonates; the incidence remains unclear due to the absence of a unified definition of AKI in this population and because previous studies have varied greatly in screening for AKI with serum creatinine and urine output assessments. Premature infants may be born with less than half of the nephrons compared with term neonates, predisposing them to chronic kidney disease (CKD) early on in life and as they age. AKI can also lead to CKD, and premature infants with AKI may be at very high risk for long-term kidney problems. AKI in neonates is often multifactorial and may result from prenatal, perinatal, or postnatal insults as well as any combination thereof. This review focuses on the causes of AKI, the importance of early detection, the management of AKI in neonates, and long-term sequela of AKI in neonates.

As advances in Critical Care Medicine continue, critically ill patients are surviving despite the severity of their illness. The incidence of acute kidney injury (AKI) has increased, and its impact on clinical outcomes as well as medical expenditures has been established. The role, indications and technological advancements of renal replacement therapy (RRT) have evolved, allowing more effective therapies with less complications. With these changes, Critical Care Nephrology has become an established specialty, and ongoing collaborations between critical care physicians and nephrologist have improved education of multi-disciplinary team members and patient care in the ICU. Multidisciplinary programs to support these changes have been stablished in some hospitals to maximize the delivery of care, while other programs have continue to struggle in their ability to acquire the necessary resources to maximize outcomes, educate their staff, and develop quality initiatives to evaluate and drive improvements. Clearly, the role of the nephrologist in the ICU has evolved, and varies widely among institutions. This special article will provide insights that will hopefully optimize the role of the nephrologist as the leader of the acute care nephrology program, as clinician for critically ill patients, and as teacher for all members of the health care team.

In a population of neonatal and pediatric patients on extracorporeal membrane oxygenation; to describe the prevalence and timing of acute kidney injury utilizing a consensus acute kidney injury definition and investigate the association of acute kidney injury with outcomes (length of extracorporeal membrane oxygenation and mortality).Multicenter retrospective observational cohort study.Six pediatric extracorporeal membrane oxygenation centers.Pediatric patients (age,18 yr) on extracorporeal membrane oxygenation at six centers during a period of January 1, 2007, to December 31, 2011.None.Complete data were analyzed for 832 patients on extracorporeal membrane oxygenation. Sixty percent of patients had acute kidney injury utilizing the serum creatinine Kidney Disease Improving Global Outcomes criteria (AKI) and 74% had acute kidney injury using the full Kidney Disease Improving Global Outcomes criteria including renal support therapy (AKI). Of those who developed acute kidney injury, it was present at extracorporeal membrane oxygenation initiation in a majority of cases (52% AKI and 65% AKI) and present by 48 hours of extracorporeal membrane oxygenation support in 86% (AKI) and 93% (AKI). When adjusted for patient age, center of support, mode of support, patient complications and preextracorporeal membrane oxygenation pH, the presence of acute kidney injury by either criteria was associated with a significantly longer duration of extracorporeal membrane oxygenation support (AKI, 152 vs 110 hr; AKI, 153 vs 99 hr) and increased adjusted odds of mortality at hospital discharge (AKI: odds ratio, 1.77; 1.22-2.55 and AKI: odds ratio, 2.50; 1.61-3.90). With the addition of renal support therapy to the model, acute kidney injury was associated with a longer duration of extracorporeal membrane oxygenation support (AKI, 149 vs 121 hr) and increased risk of mortality at hospital discharge (AKI: odds ratio, 1.52; 1.04-2.21).Acute kidney injury is present in 60-74% of neonatal-pediatric patients supported on extracorporeal membrane oxygenation and is present by 48 hours of extracorporeal membrane oxygenation support in 86-93% of cases. Acute kidney injury has a significant association with increased duration of extracorporeal membrane oxygenation support and increased adjusted odds of mortality at hospital discharge.

Background Bronchopulmonary dysplasia (BPD) portends lifelong organ impairment and death. Our ability to predict BPD in first days of life is limited, but could be enhance using novel biomarkers. Methods Using an available clinical and urine biomarker database obtained from a prospective 113 infant cohort (birth weight ≤1200 g and/or gestational age ≤31 weeks), we evaluated the independent association of 14 urine biomarkers with BPD/mortality. Results Two of the 14 urine biomarkers were independently associated with BPD/mortality after controlling for gestational age (GA), small for gestational age (SGA), and intubation status. The best performing protein was clusterin, a ubiquitously expressed protein and potential sensor of oxidative stress associated with lung function in asthma patients. When modeling for BPD/mortality, the independent odds ratio for maximum adjusted urine clusterin was 9.2 (95% CI 3.3 - 32.8, P

BACKGROUND: We evaluated the epidemiology of fluid balance (FB) over the first postnatal week and its impact on outcomes in a multi-center cohort of premature neonates from the AWAKEN study. METHODS: Retrospective analysis of infants