Selective Cytopheretic Device Use in Continuous Kidney Replacement Therapy in Children: A Cohort Study With a Historical Comparator.

Rationale and Objective: Critically ill children with acute kidney injury (AKI) requiring continuous renal replacement therapy (CRRT) are at increased risk of death. The selective cytopheretic device (SCD) promotes an immunomodulatory effect at circuit-ionized calcium of <0.40 mmol/L. In an adult CRRT patient study, SCD-treated patients reported improved survival or dialysis independence. We reported safety data from children who received CRRT-SCD therapy and compared outcomes with a historic pediatric CRRT cohort. Study Design: We performed 2 prospective multicenter studies to evaluate the safety and feasibility of SCD in critically ill children. Setting and Participants: Four pediatric institutions enrolled children weighing 10 kg or more with AKI and multi-organ dysfunction receiving CRRT as the standard of care with the SCD-integrated post-CRRT membrane. Exposure: Patients received CRRT-SCD with regional citrate anticoagulation for up to 7-10 days, or CRRT discontinuation, whichever came first. Analytical Approach: We reported serious adverse events among patients and CRRT-SCD-related process and outcome variables. We compared survival to intensive care unit (ICU) discharge rates between the CRRT-SCD cohort and a matched cohort from the prospective pediatric CRRT registry, using odds ratios in multivariable analysis for factors associated with prospective pediatric CRRT patient ICU mortality. To validate these crude analyses, Bayesian logistic regression was performed to assess for attributable benefit-risk assessment of the SCD. Results: Twenty-two patients received CRRT-SCD treatments. Fifteen serious adverse events were recorded; none were SCD-related. Seventeen patients survived till ICU discharge or day 60. Both multivariable and Bayesian analyses revealed a probable benefit of the addition of SCD. Fourteen of the 16 patients surviving ICU discharge reported a normal estimated glomerular filtration rate and no patient was dialysis dependent at 60 days. Limitations: The study had a few limitations, such as (1) a small sample size in the SCD-PED cohort group; (2) unchanging historic control group; and (3) adverse events were not recorded in the control group. Conclusions: The SCD therapy is feasible, safe, and demonstrates probable benefit for critically ill children who require CRRT for AKI.

Only 50% of critically ill children with kidney failure who require the most advanced forms of dialysis survive. One cause of this poor survival is the increased activation of the immune system, which leads to inflammation and organ failure. Reducing the effects of inflammation could improve the survival rate in this very sick population. We studied a device, the selective cytopheretic device (SCD) that lessens the activity of cells in the body that cause inflammation. Twenty-two children received treatment with the SCD put in line with a standard dialysis machine, of which 17 (77%) survived (compared to the expected 11). There were no adverse effects noted with the SCD. Hence, we suggest that the SCD offers an option to improve outcomes in critically ill children with kidney failure.

Perinatal risk factors associated with acute kidney injury severity and duration among infants born extremely preterm.

BACKGROUND: We evaluated time-varying perinatal risk factors associated with early (≤7 post-natal days) and late (>7 post-natal days) severe acute kidney injury (AKI) occurrence and duration. METHODS: A secondary analysis of Preterm Erythropoietin Neuroprotection Trial data. We defined severe AKI (stage 2 or 3) per neonatal modified Kidney Disease: Improving Global Outcomes criteria. Adjusted Cox proportional hazards models were conducted with exposures occurring at least 72 h before severe AKI. Adjusted negative binomial regression models were completed to evaluate risk factors for severe AKI duration. RESULTS: Of 923 participants, 2% had early severe AKI. In the adjusted model, gestational diabetes (adjusted HR (aHR) 5.4, 95% CI 1.1-25.8), non-steroidal anti-inflammatory drugs (NSAIDs) (aHR 3.2, 95% CI 1.0-9.8), and vancomycin (aHR 13.9, 95% CI 2.3-45.1) were associated with early severe AKI. Late severe AKI occurred in 22% of participants. Early severe AKI (aHR 2.5, 95% CI 1.1-5.4), sepsis (aHR 2.5, 95% CI 1.4-4.4), vasopressors (aHR 2.9, 95% CI 1.8-4.6), and diuretics (aHR 2.6, 95% CI 1.9-3.6) were associated with late severe AKI. Participants who had necrotizing enterocolitis or received NSAIDs had longer severe AKI duration. CONCLUSION: We identified major risk factors for severe AKI that can be the focus of future research. IMPACT STATEMENT: Time-dependent risk factors for severe acute kidney injury (AKI) and its duration are not well defined among infants born <28 weeks' gestation. Over 1 in 5 infants born <28 weeks' gestation experienced severe AKI, and this study identified several major time-dependent perinatal risk factors occurring within 72 h prior to severe AKI. This study can support efforts to develop risk stratification and clinical decision support to help mitigate modifiable risk factors to reduce severe AKI occurrence and duration.

Deriving and validating a protocol to determine the need for prophylactic peritoneal dialysis in neonates after cardiopulmonary bypass surgery.

BACKGROUND: Prophylactic peritoneal dialysis (PD) in neonates undergoing cardiopulmonary bypass (CPB) is safe and improves outcomes. We sought to (1) derive the pre-operative characteristics of neonates who are most likely to benefit from PD after CPB and (2) validate a new prophylactic PD protocol based on our retrospective analysis. METHODS: First, we retrospectively evaluated neonates requiring cardiac surgery with CPB from October 2012 to June 2016. We categorized neonates as those who "needed PD" and those who "did not need PD" based on prior experience with neonates requiring kidney support therapy. Pre-operative serum creatinine ≥ 0.8 mg/dL, pre-operative weight ≤ 2.5 kg, or having an open chest post-operatively were independently associated with "needed PD." Next, beginning in March 2019, we implemented a new prophylactic PD protocol in which only those who met at least one of the three criteria derived in the retrospective analysis had a PD catheter placed in the OR. RESULTS: In Era 2, after the implementation of a new prophylactic PD protocol, 100% of neonates in the "needed PD" group had a PD catheter placed in the OR, which was more than in the prior era (Era 1 = 86.6%) (p = 0.05). Only 26.1% in the "did not need PD" group had a PD catheter placed in the OR which was less than in the prior era (Era 1 = 50.6%) (p < 0.01). CONCLUSIONS: We successfully developed and implemented an evidence-based prophylactic PD protocol that has improved our ability to provide prophylactic PD in neonates after CPB.

Incidence, Risk Factors, and Outcomes Associated With Recurrent Neonatal Acute Kidney Injury in the AWAKEN Study.

Importance: The incidence and associated outcomes of recurrent acute kidney injury (rAKI) in neonates remain largely unknown. Objective: To determine the incidence, risk factors, and clinical outcomes associated with rAKI in critically ill neonates. Design, Setting, and Participants: This cohort study was a secondary analysis of the multicenter, international Assessment of Worldwide Acute Kidney Injury Epidemiology in Neonates retrospective study. Comparisons were made among neonates with no AKI, a single AKI episode (sAKI), and rAKI. All neonates younger than 14 days who were admitted between January 1 and March 31, 2014, to 24 participating level II to IV neonatal intensive care units and received intravenous fluids for at least 48 hours were considered for inclusion. Neonates with congenital heart disease requiring surgery within the first week of life, lethal chromosomal anomalies, death within 48 hours of admission, or severe congenital kidney abnormalities were excluded. Data were analyzed from May 23, 2022, to December 8, 2023. Exposure: Recurrent AKI using the neonatal Kidney Disease: Improving Global Outcomes criteria. Determination of each rAKI required a complete return to the baseline serum creatinine level that defined the prior AKI episode. Main Outcomes and Measures: Incidence and risk factors of rAKI and associations of rAKI with length of stay (LOS; ie, birth to hospital discharge) and mortality. Results: The study cohort (n = 2162) included 1233 male neonates (57.0%). Gestational age distribution was less than 29 weeks for 276 neonates (12.8%), 29 to less than 36 weeks for 958 (44.3%), and 36 weeks or older for 928 (42.9%). Of 605 neonates with AKI, 133 (22.0%) developed rAKI with risk factors including younger gestational age, lower birthweight, and higher stage of initial AKI. Infants with rAKI experienced longer median LOS (no AKI, 17 [IQR, 8-34] days; sAKI, 18 [IQR, 9-45] days; rAKI, 60 [IQR, 25-109] days; P < .001). Time-varying Cox proportional hazards regression models suggest rAKI is independently associated with a lower hazard of discharge (adjusted hazard ratio, 0.7 [95% CI, 0.6-0.9]; P = .01) when compared with sAKI, but mortality did not differ between groups (adjusted hazard ratio, 1.4 [95% CI, 0.6-3.0]; P = .44). Conclusions and Relevance: In this cohort study, neonatal rAKI was independently associated with longer LOS when compared with sAKI, suggesting that rAKI in neonates may be an important clinical distinction warranting further study and careful monitoring after an initial AKI episode.

Survival of Infants With Severe Congenital Kidney Disease After ECMO and Kidney Support Therapy.

Congenital kidney failure not only affects the homeostatic functions of the kidney, but also affects neonatal respiratory integrity. Until recently, extracorporeal membrane oxygenation (ECMO) support was not used in this population because the need for ECMO clearly established nonviability. Since 2016, 31 neonates have been admitted to the NICU at Children's of Alabama with congenital kidney failure. Five patients were placed on ECMO for severe respiratory distress unresponsive to conventional interventions. We evaluated neonates with congenital kidney failure and pulmonary hypoplasia/hypertension refractory to conventional therapies who received ECMO support within the first 9 postnatal days. We describe the pre and postnatal diagnoses, ECMO course details, dialysis modalities, complications, procedures, and long-term outcomes of these patients. All 5 patients received kidney support therapy by postnatal day 7. Diagnoses included posterior urethral valves, bilateral renal dysplasia, and autosomal recessive polycystic kidney disease. Gestational age ranged from 35.6 to 37.1 weeks. Birth weight ranged from 2740 to 3140 g. Days on ECMO ranged from 4 to 23. Four survived and are living today. Pulmonary hypertension resolved in surviving patients. Three surviving patients require no oxygen support, and 1 patient requires nocturnal oxygen. Three survivors received a kidney transplant, and 1 awaits transplant evaluation. Patients with congenital kidney failure with severe pulmonary hypoplasia/pulmonary hypertension no longer warrant a reflexive assignment of nonviability. Meticulous ECMO, respiratory, nutritional, and kidney support therapies may achieve a favorable long-term outcome. Further investigation of strategies for optimal outcome is needed.

Caffeine and kidney function at two years in former extremely low gestational age neonates.

BACKGROUND: Extremely low gestational age neonates (ELGANs) are at risk for chronic kidney disease. The long-term kidney effects of neonatal caffeine are unknown. We hypothesize that prolonged caffeine exposure will improve kidney function at 22-26 months. METHODS: Secondary analysis of the Preterm Erythropoietin Neuroprotection Trial of neonates <28 weeks' gestation. Participants included if any kidney outcomes were collected at 22-26 months corrected age. Exposure was post-menstrual age of caffeine discontinuation. PRIMARY OUTCOMES: 'reduced eGFR' <90 ml/min/1.73 m2, 'albuminuria' (>30 mg albumin/g creatinine), or 'elevated blood pressure' (BP) >95th %tile. A general estimating equation logistic regression model stratified by bronchopulmonary dysplasia (BPD) status was used. RESULTS: 598 participants had at least one kidney metric at follow up. Within the whole cohort, postmenstrual age of caffeine discontinuation was not associated with any abnormal measures of kidney function at 2 years. In the stratified analysis, for each additional week of caffeine, the no BPD group had a 21% decreased adjusted odds of eGFR <90 ml/min/1.73m2 (aOR 0.78; CI 0.62-0.99) and the BPD group had a 15% increased adjusted odds of elevated BP (aOR 1.15; CI: 1.05-1.25). CONCLUSIONS: Longer caffeine exposure during the neonatal period is associated with differential kidney outcomes at 22-26 months dependent on BPD status. IMPACT: In participants born <28 weeks' gestation, discontinuation of caffeine at a later post menstrual age was not associated with abnormal kidney outcomes at 22-26 months corrected age. When assessed at 2 years of age, later discontinuation of caffeine in children born <28 weeks' gestation was associated with a greater risk of reduced eGFR in those without a history of BPD and an increased odds of hypertension in those with a history of BPD. More work is necessary to understand the long-term impact of caffeine on the developing kidney.

Receipt of high-frequency ventilation is associated with acute kidney injury in very preterm neonates.

BACKGROUND: High-frequency ventilation (HFV) is frequently used in critically ill preterm neonates. We aimed to determine the incidence of acute kidney injury (AKI) in neonates less than 29 weeks gestation who received HFV in the first week of life and to determine if the rates of AKI differed in those who received other forms of respiratory support. METHODS: This retrospective cohort study of 24 international, level III/IV neonatal intensive care units (NICUs) included neonates less than 29 weeks gestation from the AWAKEN study database. Exclusion criteria included the following: no intravenous fluids ≥ 48 h, admission ≥ 14 days of life, congenital heart disease requiring surgical repair at < 7 days of life, lethal chromosomal anomaly, death within 48 h, severe congenital kidney abnormalities, inability to determine AKI status, insufficient data on ventilation, and when the diagnosis of early AKI was unable to be made. Subjects were grouped into three groups based on ventilation modes (CPAP/no ventilation, conventional ventilation, and HFV). RESULTS: The incidence of AKI was highest in the CPAP/no ventilation group, followed by HFV, followed by conventional ventilation (CPAP/no ventilation 48.5% vs. HFV 42.6% vs. conventional ventilation 28.4% (p = 0.009). An increased risk for AKI was found for those on HFV compared to CPAP/no ventilation (HR = 2.65; 95% CI:1.22-5.73). CONCLUSIONS: HFV is associated with AKI in the first week of life. Neonates on HFV should be screened for AKI. The reasons for this association are not clear. Further studies should evaluate the relationship between ventilator strategies and AKI in premature neonates. A higher resolution version of the Graphical abstract is available as Supplementary information.

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.

Association Between Urinary Biomarkers and CKD in Extremely Low Gestational Age Neonates.

RATIONALE & OBJECTIVE: Children born before 28 weeks' gestation are at increased risk of chronic kidney disease (CKD). Urine biomarkers may shed light on mechanistic pathways and improve the ability to forecast CKD. We evaluated whether urinary biomarkers in neonates of low gestational age (GA) are associated with a reduced estimated glomerular filtration rate (eGFR) over time. STUDY DESIGN: A cohort study of neonates with an exploratory case-control study of a subset of the cohort. SETTING & PARTICIPANTS: 327 neonates born at 24-27 weeks' gestation with 2-year eGFR data from the PENUT (Preterm Erythropoietin Neuroprotection Trial) and the REPaIReD (Recombinant Erythropoietin for Prevention of Infant Renal Disease) study. EXPOSURES: 11 urinary biomarkers measured at 27, 30, and 34 weeks' postmenstrual age for the primary cohort study and 10 additional biomarkers for the exploratory case-control study. OUTCOMES: eGFR<90mL/min/1.73m2 at 2 years corrected for GA. ANALYTICAL APPROACH: Linear mixed models to assess differences in biomarker values between neonates in whom CKD did and did not develop, accounting for multiple comparisons using Bonferroni-Holm correction in the cohort study only. Cohort analyses were adjusted for sex, GA, and body mass index. Cases were matched to controls on these variables in the case-control study. RESULTS: After adjusting for weeks of GA, urinary levels of α-glutathione-S-transferase (log difference, 0.27; 95% CI, 0.12-0.43), albumin (log difference, 0.13; 95% CI, 0.02-0.25), and cystatin C (log difference, 0.19; 95% CI, 0.04-0.34) were higher in those in whom CKD developed than in those in whom it did not. Urinary albumin and cystatin C levels did not remain significantly different after Bonferroni-Holm correction. In the exploratory case-control analysis, there were no differences in any biomarkers between cases and controls. LIMITATIONS: Early deaths and a high number of subjects without eGFR at 2 years corrected for GA. CONCLUSIONS: Measurement of urinary biomarkers may assist in monitoring neonates who are at risk for CKD. Additional studies are needed to confirm these findings. FUNDING: Grants from government (National Institutes of Health). TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT01378273. PLAIN-LANGUAGE SUMMARY: Approximately 15 million neonates worldwide are born prematurely, and 2 million are born before 28 weeks' gestation. Many of these children go on to experience chronic kidney disease. Urine biomarkers may allow for early recognition of those at risk for the development of kidney disease. In this study of more than 300 children born before 28 weeks' gestational age, we found higher mean urinary levels of α-glutathione-S-transferase at 27, 30, and 34 weeks in children whose estimated glomerular filtration rate was<90mL/min/1.73m2 at 2 years compared with children whose estimated glomerular filtration rate was>90mL/min/1.73m2 at 2 years. Measurement of urinary biomarkers may assist in monitoring neonates who are at risk for chronic kidney disease. Additional studies are needed to confirm our findings.

Programs and processes for advancing pediatric acute kidney support therapy in hospitalized and critically ill children: a report from the 26th Acute Disease Quality Initiative (ADQI) consensus conference.

Pediatric acute kidney support therapy (paKST) programs aim to reliably provide safe, effective, and timely extracorporeal supportive care for acutely and critically ill pediatric patients with acute kidney injury (AKI), fluid and electrolyte derangements, and/or toxin accumulation with a goal of improving both hospital-based and lifelong outcomes. Little is known about optimal ways to configure paKST teams and programs, pediatric-specific aspects of delivering high-quality paKST, strategies for transitioning from acute continuous modes of paKST to facilitate rehabilitation, or providing effective short- and long-term follow-up. As part of the 26th Acute Disease Quality Initiative Conference, the first to focus on a pediatric population, we summarize here the current state of knowledge in paKST programs and technology, identify key knowledge gaps in the field, and propose a framework for current best practices and future research in paKST.

Prospective Study of the Multisite Spread of a Medication Safety Intervention: Factors Common to Hospitals With Improved Outcomes.

Context and implementation approaches can impede the spread of patient safety interventions. The objective of this article is to characterize factors associated with improved outcomes among 9 hospitals implementing a medication safety intervention. Nephrotoxic Injury Negated by Just-in-Time Action (NINJA) is a pharmacist-driven intervention that led to a sustained reduction in nephrotoxic medication-associated acute kidney injury (NTMx-AKI) at 1 hospital. Using qualitative comparative analysis, the team prospectively assessed the association between context and implementation factors and NTMx-AKI reduction during NINJA spread to 9 hospitals. Five hospitals reduced NTMx-AKI. These 5 had either (1) a pharmacist champion and >2 pharmacists working on NINJA (Scon 1.0, Scov 0.8) or (2) a nephrologist-implementing NINJA with minimal competing organizational priorities (Scon 1.0, Scov 0.2). Interviews identified ways NINJA team leaders obtained pharmacist support or successfully implemented without that support. In conclusion, these findings have implications for future spread of NINJA and suggest an approach to study spread of safety interventions more broadly.

Recent Advances in Kidney Replacement Therapy in Infants: A Review.

Kidney replacement therapy (KRT) is used to treat children and adults with acute kidney injury (AKI), fluid overload, kidney failure, inborn errors of metabolism, and severe electrolyte abnormalities. Peritoneal dialysis and extracorporeal hemodialysis/filtration can be performed for different durations (intermittent, prolonged intermittent, and continuous) through either adaptation of adult devices or use of infant-specific devices. Each of these modalities have advantages and disadvantages, and often multiple modalities are used depending on the scenario and patient-specific needs. Traditionally, these therapies have been challenging to deliver in infants due the lack of infant-specific devices, small patient size, required extracorporeal volumes, and the risk of hemodynamic stability during the initiation of KRT. In this review, we discuss challenges, recent advancements, and optimal approaches to provide KRT in hospitalized infants, including a discussion of peritoneal dialysis and extracorporeal therapies. We discuss each specific KRT modality, review newer infant-specific devices, and highlight the benefits and limitations of each modality. We also discuss the ethical implications for the care of infants who need KRT and areas for future research.

Clinical Characteristics and Outcomes of Drug-Induced Acute Kidney Injury Cases.

Introduction: Drug-induced acute kidney injury (DI-AKI) is a frequent adverse event. The identification of DI-AKI is challenged by competing etiologies, clinical heterogeneity among patients, and a lack of accurate diagnostic tools. Our research aims to describe the clinical characteristics and predictive variables of DI-AKI. Methods: We analyzed data from the Drug-Induced Renal Injury Consortium (DIRECT) study (NCT02159209), an international, multicenter, observational cohort study of enriched clinically adjudicated DI-AKI cases. Cases met the primary inclusion criteria if the patient was exposed to at least 1 nephrotoxic drug for a minimum of 24 hours prior to AKI onset. Cases were clinically adjudicated, and inter-rater reliability (IRR) was measured using Krippendorff's alpha. Variables associated with DI-AKI were identified using L1 regularized multivariable logistic regression. Model performance was assessed using the area under the receiver operating characteristic curve (ROC AUC). Results: A total of 314 AKI cases met the eligibility criteria for this analysis, and 271 (86%) cases were adjudicated as DI-AKI. The majority of the AKI cases were recruited from the United States (68%). The most frequent causal nephrotoxic drugs were vancomycin (48.7%), nonsteroidal antiinflammatory drugs (18.2%), and piperacillin/tazobactam (17.8%). The IRR for DI-AKI adjudication was 0.309. The multivariable model identified age, vascular capacity, hyperglycemia, infections, pyuria, serum creatinine (SCr) trends, and contrast media as significant predictors of DI-AKI with good performance (ROC AUC 0.86). Conclusion: The identification of DI-AKI is challenging even with comprehensive adjudication by experienced nephrologists. Our analysis identified key clinical characteristics and outcomes of DI-AKI compared to other AKI etiologies.

Hemolytic Uremic Syndrome-Induced Acute Kidney Injury Treated via Immunomodulation with the Selective Cytopheretic Device.

INTRODUCTION: Shiga-toxin associated-hemolytic uremic syndrome (STEC-HUS) is a severe cause of acute kidney injury (AKI) in children. Although most children recover, about 5% die and 30% develop chronic renal morbidity. HUS pathophysiology includes activated neutrophils damaging vascular endothelial cells. Therapeutic immunomodulation of activated neutrophils may alter the progression of disease. We present 3 pediatric patients treated with the selective cytopheretic device (SCD). METHODS: We describe a 12 y.o. (patient 1) and two 2 y.o. twins (patients 2 and 3) with STEC-HUS requiring continuous renal replacement therapy (CRRT) who were enrolled in two separate studies of the SCD. RESULTS: Patient 1 presented with STEC-HUS causing AKI and multisystem organ failure and received 7 days of SCD and CRRT treatment. After SCD initiation, the patient had gradual recovery of multi-organ dysfunction, with normal kidney and hematologic parameters at 60-day follow-up. Patients 2 and 3 presented with STEC-HUS with AKI requiring dialysis. Each received 24 h of SCD therapy. Thereafter, both gradually improved, with normalization (patient 2) and near-normalization (patient 3) of kidney function at 60-day follow-up. CONCLUSION: Immunomodulatory treatment with the SCD was associated with improvements in multisystem stigmata of STEC-HUS-induced AKI and was well-tolerated without any device-related adverse events.

Acute Kidney Injury Defined by Fluid-Corrected Creatinine in Premature Neonates: A Secondary Analysis of the PENUT Randomized Clinical Trial.

Importance: Acute kidney injury (AKI) and disordered fluid balance are common in premature neonates; a positive fluid balance dilutes serum creatinine, and a negative fluid balance concentrates serum creatinine, both of which complicate AKI diagnosis. Correcting serum creatinine for fluid balance may improve diagnosis and increase diagnostic accuracy for AKI. Objective: To determine whether correcting serum creatinine for fluid balance would identify additional neonates with AKI and alter the association of AKI with short-term and long-term outcomes. Design, Setting, and Participants: This study was a post hoc cohort analysis of the Preterm Erythropoietin Neuroprotection Trial (PENUT), a phase 3, randomized clinical trial of erythropoietin, conducted at 19 academic centers and 30 neonatal intensive care units in the US from December 2013 to September 2016. Participants included extremely premature neonates born at less than 28 weeks of gestation. Data analysis was conducted in December 2022. Exposure: Diagnosis of fluid-corrected AKI during the first 14 postnatal days, calculated using fluid-corrected serum creatinine (defined as serum creatinine multiplied by fluid balance [calculated as percentage change from birth weight] divided by total body water [estimated 80% of birth weight]). Main Outcomes and Measures: The primary outcome was invasive mechanical ventilation on postnatal day 14. Secondary outcomes included death, hospital length of stay, and severe bronchopulmonary dysplasia (BPD). Categorical variables were analyzed by proportional differences with the χ2 test or Fisher exact test. The t test and Wilcoxon rank sums test were used to compare continuous and ordinal variables, respectively. Odds ratios (ORs) and 95% CIs for the association of exposure with outcomes of interest were estimated using unconditional logistic regression models. Results: A total of 923 premature neonates (479 boys [51.9%]; median [IQR] birth weight, 801 [668-940] g) were included, of whom 215 (23.3%) received a diagnosis of AKI using uncorrected serum creatinine. After fluid balance correction, 13 neonates with AKI were reclassified as not having fluid-corrected AKI, and 111 neonates previously without AKI were reclassified as having fluid-corrected AKI (ie, unveiled AKI). Therefore, fluid-corrected AKI was diagnosed in 313 neonates (33.9%). Neonates with unveiled AKI were similar in clinical characteristics to those with AKI whose diagnoses were made with uncorrected serum creatinine. Compared with those without AKI, neonates with unveiled AKI were more likely to require ventilation (81 neonates [75.0%] vs 254 neonates [44.3%] and have longer hospital stays (median [IQR], 102 [84-124] days vs 90 [71-110] days). In multivariable analysis, a diagnosis of fluid-corrected AKI was associated with increased odds of adverse clinical outcomes, including ventilation (adjusted OR, 2.23; 95% CI, 1.56-3.18) and severe BPD (adjusted OR, 2.05; 95% CI, 1.15-3.64). Conclusions and Relevance: In this post hoc cohort study of premature neonates, fluid correction increased the number of premature neonates with a diagnosis of AKI and was associated with increased odds of adverse clinical outcomes, including ventilation and BPD. Failing to correct serum creatinine for fluid balance underestimates the prevalence and impact of AKI in premature neonates. Future studies should consider correcting AKI for fluid balance. Trial Registration: ClinicalTrials.gov Identifier: NCT01378273.

Risk of chronic kidney disease in children who developed acute kidney injury secondary to nephrotoxic medication exposure in infancy.

INTRODUCTION: Nephrotoxic medication (NTM) is one of the common causes of acute kidney injury (AKI) in critically ill infants. Current knowledge about the long-term effects of NTM exposure and associated AKI during the neonatal period and early infancy is limited. Hence, we aimed to explore the risk of chronic kidney disease (CKD) after NTM-AKI in this age group. METHODS: We performed a cross-sectional study including children 2-7 years of age, who had a history of high NTM exposure during NICU hospitalization. Cases and controls were defined as children who developed AKI and who did not develop AKI after NTM exposure, respectively. The primary outcome of interest was to explore the prevalence of composite CKD. In addition, we explored differences in urinary biomarker kidney injury molecule-1 (KIM-1) between the groups. RESULTS: We enrolled 48 children, 18 cases and 30 controls in which 25/48 (52%) had at least one finding of CKD. The composite CKD outcome tended to be higher in cases vs controls (61.1% vs. 46.6%, odds ratio = 1.79 (95% confidence interval 0.54-5.8)); however, this was not statistically significant. Median urinary KIM-1 value trended higher in controls, 0.367(0.23-0.59) vs. 0.20 (IQR 0.11-0.47), which was not statistically significant. CONCLUSION: In this study, 52% of children exposed to NTM had at least one marker of CKD at a median age of 5 years. Multicenter, large prospective studies are needed to improve our understanding of the natural course of NTM-AKI and to determine risk factors and strategies to reduce CKD in this high-risk population.

Neonatal nephrotoxic medication exposure and early acute kidney injury: results from the AWAKEN study.

BACKGROUND: We aimed to describe nephrotoxic medication exposure and investigate associations between exposure and acute kidney injury (AKI) in the neonatal intensive care unit during the first postnatal week. DESIGN/METHODS: Secondary analysis of the AWAKEN cohort. We evaluated nephrotoxic medication exposure during the first postnatal week and associations with AKI using time-varying Cox proportional hazard regressions models. Nephrotoxic medication exposure categories were defined as: no nephrotoxic medication, nephrotoxic medications excluding aminoglycosides, aminoglycoside alone, and aminoglycoside and another nephrotoxic medication. RESULTS: Of 2162 neonates, 1616 (74.7%) received ≥1 nephrotoxic medication. Aminoglycoside receipt was most common (72%). AKI developed in 211(9.8%) neonates and was associated with a nephrotoxic medication exposure (p < 0.01). Nephrotoxic medication exposures including a nephrotoxic medication excluding aminoglycoside (aHR 3.14, 95% CI 1.31-7.55) and aminoglycoside and  another nephrotoxic medication (aHR 4.79, 95% CI 2.19-10.50) were independently associated with AKI and severe AKI (stage 2/3), respectively. CONCLUSIONS: Nephrotoxic medication exposure in critically ill infants is common during the first postnatal week. Specific nephrotoxic medication exposure, principally aminoglycosides with another nephrotoxic medication, are independently associated with early AKI.