Improving Continuous kidney replacement therapy (CKRT) Outcomes in Neonates and Infants Through Interdis ciplinary Collaboration (ICONIIC) is a multicenter quality improvement and research registry. We aimed to identify programmatic structures and educational practices for neonatal and infant CKRT. A survey focusing on care delivery and models, units offering therapy, staff-to-patient ratios, and education protocols was distributed to institutions in ICONIIC using the Carpediem machine. Of the 13 responding sites, 11 used the Carpediem machine in Pediatric Intensive Care Units (ICUs), 9 in Neonatal ICUs, and 8 in Cardiac ICUs. A collaborative care model was most common (69.2%). While education practices varied, all sites required nurse-specific training, and all but one mandated provider oversight during CKRT initiation. Understanding these practices may inform best practices for neonatal and infant CKRT.

Oxcarbazepine (OXZ) is an antiepileptic drug whose pharmacological effect is primarily mediated by its active metabolite, 10-monohydroxy derivative (MHD). OXZ is approved for use in adults and children older than 2 years with an age- and body weight-tiered dosing recommendation, but dosing guidance for children with obesity is lacking. This work aimed to assess the dosing requirements of OXZ in children with obesity to support label extension. Two multicenter studies (NCT01431326 and NCT02993861) were conducted in patients receiving standard-of-care OXZ therapy. Participants ≥ 2 years of age with a body mass index ≥ 95th percentile were classified as obese. Plasma concentrations were measured by a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) assay. Nonlinear mixed effects modeling was performed using NONMEM 7.4 to characterize the population pharmacokinetics of OXZ and MHD simultaneously. Simulations were performed to compare MHD systemic exposure in children ≥ 2 years of age with and without obesity. One hundred study participants with a median (range) age of 9 years (44 days–20.90 years) contributed 425 plasma concentrations of OXZ (n = 212) and MHD (n = 213). Fifty-two percent of the participants had obesity. A one-compartment joint parent–metabolite model with linear input–output and bi-directional transformation between OXZ and MHD best characterized the pharmacokinetics. Body size was the only covariate affecting pharmacokinetics, and a fat-free mass–based metric termed pharmacokinetic weight (PKWT) best characterized that effect allometrically. Simulation results revealed that the current dosing regimen of OXZ can produce comparable exposure of MHD in children ≥ 2 years of age with and without obesity. A model-informed analysis confirms that the current pediatric dosing regimen of OXZ applies to children in general, regardless of their obesity status.

Background: The well-known accuracy limitations of estimated GFR (eGFR) currently employed in clinical practice present barriers to optimal care for patients with, or at-risk for, decreased kidney function. A point-of-care glomerular filtration rate (GFR) measurement methodology has the potential to address these limitations. We prospectively assessed transdermal detection of the novel fluorescent GFR tracer agent relmapirazin in participants having normal or impaired kidney function across all human skin colors on the Fitzpatrick Skin Scale (FSS). Methods: A multi-center study comprising 74 participants with eGFR from normal to Stage 4 CKD was performed. Forty-six participants were FSS types I-III, and twenty-eight were FSS type IV-VI. A module containing an LED and photodetector to activate and collect transdermal relmapirazin fluorescence was attached adhesively to the upper chest of each participant. Relmapirazin (1.5mg/kg) was administered by intravenous push, and fluorescence emission was acquired for 12 hours. A two-compartment pharmacokinetic model fit the fluorescent intensity vs time data, and the fluorescence clearance rate (FCR) was extracted from the second (terminal) compartment. Plasma relmapirazin concentrations were measured contemporaneously and the corresponding plasma GFR for each participant was determined. Linear regression analysis was used to compare the FCR to the indexed plasma GFR. Results: Participant age range was 23 to 80 years old, with 59% females. The two-compartment pharmacokinetic behavior was observed in the fluorescence intensity vs time data and a FCR was successfully deduced for every participant completing the 12-hour study. The FCR vs. the indexed plasma GFR yielded an excellent correlation over the range of GFR measured and for all skin colors with a r2 = 0.90 (95% confidence interval 0.85 to 0.94). No severe adverse events were reported. Conclusions: Point-of-care transdermal detection of the fluorescent GFR tracer agent relmapirazin was feasible in patients with normal to impaired kidney function and for a range of skin color types.

AIMS:The Selective Cytopheretic Device for Pediatrics (SCD-PED) is a cell-directed extracorporeal therapy approved by the Food and Drug Administration through the humanitarian device exemption pathway for patients≥10kg, age≤22 years with acute kidney injury due to sepsis or a septic condition requiring antibiotics and on continuous renal replacement therapy (CRRT). We leveraged the Kids' Inpatient Database (KID) and SCD-PED study data to estimate hospitalization costs with and without SCD-PED therapy. MATERIALS AND METHODS:A cost regression model was built from KID hospitalizations (2019) that included patients aged 1-20 years with AKI receiving CRRT, total parenteral nutrition, KID mortality risk=4, KID severity=4, and hospital length of stay (LOS) ≤60 days. Data assessed as cost predictors included patient age, sex, vasopressor use, mechanical ventilation, sepsis, theoretical SCD-PED cost/number used, LOS, and death at hospital discharge. Differences in mean costs between a matched control cohort from the Prospective Pediatric CRRT registry (ppCRRT) and the SCD-PED study cohort were estimated from the model using SCD-PED study mortality rates and LOS reported in the SCD-PED studies. RESULTS:Modeled hospitalization costs were $457,092 in KID cohort (N = 106), reflecting comparable heterogeneity and complexity. Modeled hospitalization costs were $389,451 in ppCRRT (N = 210). Median hospital LOS was lower in the SCD-PED group (N = 22): 28 days vs. 31 days in the control group, which despite the lower mortality rate, resulted in a lower estimated cost of $320,304, reflecting an estimated savings of $69,146 per hospitalization. LIMITATIONS:The model in the current study compares patients using SCD-PED to an external control cohort with similar characteristics, because controls were not examined in the original clinical studies. This study is not intended to be predictive of costs in other patient types or larger populations. Additional study is needed. CONCLUSIONS:The SCD-PED is likely cost-beneficial in critically ill children with AKI requiring CRRT, including those with sepsis.

INTRODUCTION:Recent studies have identified an association between regional citrate anticoagulation (RCA) and subsequent infectious complications during continuous renal replacement therapy (CRRT). We aimed to determine if RCA was associated with infectious complications in children and young adults receiving CRRT. METHODS:A secondary analysis of the multinational Worldwide Exploration of Renal Replacement Outcomes Collaborative in Kidney Disease (WE-ROCK) registry (34 centers, 9 countries), was performed, including patients from 2015 to 2018. Patients were excluded if they (1) died within 72 h of CRRT initiation, had minor trauma or were postsurgical (analysis 1), or (2) met an exclusion in analysis 1 or had sepsis prior to CRRT initiation or chronic immunosuppression (analysis 2). Multivariable mixed-effects logistic (analysis 1) and mixed-effects Cox regression (analysis 2) were used to determine the associations between anticoagulant type and culture-positive infection after CRRT initiation. RESULTS:A total of 874 patients were included in analysis 1 and 283 in analysis 2. Culture-positive infection occurred in 25% and 17% of each analysis. In analysis 1, culture-positive infection was higher in RCA (29%) vs. heparin (23%) and other (15%); p = 0.008. There was no association between RCA and infection in multivariable analysis. In analysis 2, there was no difference in the frequency of infection by anticoagulation type. A longer time to achieve the first negative fluid balance was associated with culture-positive infection. CONCLUSION:RCA was not associated with culture-positive infection after CRRT initiation in this study. The systemic effects of AKI and longer time to first negative fluid balance may be inciting factors for an infection and represent a potentially modifiable factor that warrants future studies in this high-risk population.

Background Pediatric cardiac surgery–associated acute kidney injury is common and associated with poor outcomes, but early prediction is challenging. The purpose of this study was to determine the performance of a modified cardiac renal angina index (cRAI) in predicting adverse renal events and whether biomarker integration (urine neutrophil gelatinase–associated lipocalin) enhances cRAI performance. Methods This was a 2‐center prospective observational study in children ages 0 to 18 years admitted to the intensive care unit after cardiac surgery. The cRAI was presented as a nomogram using multivariable logistic regression to predict a composite of (1) any postoperative day 2 to 4 acute kidney injury, or (2) mechanical ventilation ≥3 days. The performance of including urine neutrophil gelatinase–associated lipocalin into the nomogram was compared with the model constructed for cRAI alone. Results Of 476 patients, 129 (27%) experienced the composite outcome, and 191 (40%) were cRAI positive. Patients who were cRAI positive were younger, had higher surgical complexity, a higher mortality rate, and longer intensive care unit length of stay. cRAI predicted the composite outcome with an optimism‐corrected area under the receiver operating characteristic curve of 0.82, sensitivity of 0.81 (95% CI, 0.73–0.87), specificity of 0.75 (95% CI, 0.70–0.80), and negative predictive value of 0.91 (95% CI, 0.87–0.94). Incorporating urine neutrophil gelatinase–associated lipocalin improved predictive performance, with an area under the receiver operating characteristic curve of 0.84, sensitivity of 0.84 (95% CI, 0.77–0.90), specificity of 0.79 (95% CI, 0.74–0.83), and negative predictive value of 0.93 (95% CI, 0.90–0.96). Conclusions The cRAI demonstrates strong predictive performance for adverse renal outcomes. Patients who were cRAI positive had worse outcomes, while the composite outcome was effectively ruled out in patients who were cRAI negative. Urine neutrophil gelatinase–associated lipocalin integration improved predictive performance parameters. cRAI holds potential for cardiac surgery–associated acute kidney injury risk stratification to enrich clinical trial enrollment.

Introduction:Acute kidney injury (AKI) definitions rely on known baseline serum creatinine (Crb), unavailable in up to 75% of hospitalized children. New equations (the AKI Baseline Creatinine [ABC] methods) for estimating Crb were derived from children without kidney disease. We aimed to externally validate ABC methods in an international cohort and assess how different Crb equations alter AKI epidemiology. Methods:AWARE was a prospective international study of critically ill children (aged 0-25 years) from 32 pediatric intensive care units (ICUs). A subset of AWARE (n = 2451) with known Crb (gold standard) was used to validate ABC methods using statistical measures of precision (R2) and accuracy (within 10% or 30% of gold standard). The entire cohort (N = 4984) was used to determine how different Crb estimating equations (3 ABC equations and 4 published estimated glomerular filtration rate [eGFR] equations imputing Crb) impact AKI incidence and its association with key clinical outcomes, including 28-day mortality, using univariate and multivariate analysis. Results:The ABC-Age equation (requiring only age) demonstrated similar accuracy and precision compared with existing Crb equations. The ABC-Creatinine equation (includes age and hospital creatinine value) outperformed existing Crb equations by up to 15% in precision (ABC-Creatinine, R2 = 0.51 vs. full-age spectrum [FAS], R2 = 0.36) and 32% in accuracy (ABC-Creatinine, 66% vs. original Schwartz, 34%). For the entire cohort, AKI incidence varied from 7% to 12%, depending on Crb definition. ABC equations were associated with clinical outcomes similarly to existing Crb equations. Conclusion:ABC-Creatinine equation (with minimal variables) outperformed existing Crb equations for accuracy and precision as the optimal method for Crb estimation. Crb definition variability alters AKI incidence and epidemiology, necessitating standardization.

INTRODUCTION:Neonatal acute kidney injury disproportionately affects extremely low birthweight (ELBW) infants (<1,000 g), who are especially vulnerable to fluid imbalance and its consequences. Current renal replacement therapy options are not optimized for patients under 2.5 kg. The Brophy Kit™, a cost-conscious, manual single-lumen dialysis device, may address this gap. METHODS:A preclinical feasibility study was conducted using eight healthy male Sprague Dawley rats (600-800 g), approximating the weight and blood volume of ELBW neonates. Each rat underwent 3-French catheter placement and sequential ultrafiltration (UF) cycles with the Brophy Kit™, targeting 5% and 10% blood volume removal. Respiratory rate was monitored as a surrogate for procedural tolerance. RESULTS:All eight animals tolerated the procedure and survived to UF completion. One rat was excluded due to catheter clotting before UF initiation. Respiratory rates remained stable throughout. Observed UF volumes deviated from prescribed volumes at the end of each experiment day by 11-12%. CONCLUSION:This proof-of-concept study demonstrates the feasibility of using the Brophy Kit™ for manual UF in a preclinical model approximating ELBW neonates. The device shows potential as an accessible solution for fluid management in resource-limited settings.

Severe malaria (SM) remains a leading cause of child mortality and an important global contributor to acute kidney injury (AKI), which can progress to chronic kidney disease (CKD) in some survivors. Notably, 80

OBJECTIVES:Sepsis-associated acute kidney injury (SAKI) is a heterogeneous syndrome associated with poor outcomes. Subphenotypes of SAKI with prognostic and therapeutic relevance have been identified in adults, but not in children. We sought to identify reproducible and clinically relevant pediatric SAKI (pSAKI) subphenotypes using readily available clinical and laboratory data. DESIGN:Secondary analysis of a retrospective observational study of pediatric sepsis. SETTING:Thirteen PICUs in the United States from January 2012 to January 2018. PATIENTS:Patients aged 0-18 years with septic shock (sepsis and requiring vasoactive medications) and day 1-2 SAKI (≥ Kidney Disease Improving Global Outcomes stage 1 by serum creatinine). INTERVENTIONS:None. MEASUREMENTS AND MAIN RESULTS:Fourteen hundred fifty-five patients were included after inclusion and exclusion criteria were applied: 873 (60%) in the derivation cohort and 582 (40%) in the external validation cohort. A two-subphenotype latent class analysis model had the best fit in both cohorts: pSAKI subphenotype 1 (pSAKI-1) and pSAKI subphenotype 2 (pSAKI-2). pSAKI-2 was characterized by younger age, more organ support, greater fluid accumulation, and laboratory evidence of inflammation, acid-base derangement, thrombocytopenia, and coagulopathy. pSAKI-2 had uniformly worse outcomes, including higher rates of severe and persistent AKI at days 3-4 (54% vs. 23%, p < 0.001) and day 7 (31% vs. 12%, p < 0.001), increased use of continuous renal replacement therapy (21% vs. 6%, p < 0.001), and independently increased odds of mortality after adjustment for potential confounders (adjusted odds ratio 1.59; 95% CI, 1.04-2.41; p = 0.03). A parsimonious classification model accurately identified pSAKI-2 membership (C-statistic 0.94 [95% CI, 0.92-0.95] and 0.85 [95% CI, 0.82-0.88], respectively, in the derivation and internal validation cohorts). CONCLUSIONS:We identified two distinct early pSAKI subphenotypes using readily available data that exhibit differential risk for poor outcomes and can be identified from a parsimonious set of variables. Pending external validation, operationalization of pSAKI subphenotypes may allow for prognostic enrichment to guide clinical care and inform clinical trial enrollment.

Introduction: Acute kidney injury (AKI) is common in critically ill neonates, including very and extremely low birth weight (VLBW, ELBW) neonates. In severe cases, kidney replacement therapy (KRT) may be warranted. Currently, available KRT devices are only indicated for those weighing >= 2.5 kg and require a double lumen or 2 separate single lumen catheters. We miniaturized the Kirpa Kit manual dialysis device, naming it the Brophy Kit, and we assessed its in vitro clearance and ultrafiltration (UF) performance. Methods: We diluted packed red blood cells to a normal hematocrit (Hct: 31.1%-36.8%) and conducted 12 clearance and 3 UF experiments. A cycle consisted of aspirating 10 ml of blood from the blood bag, passing it through a hemofilter, and returning it in a circular path. For clearance experiments, we tested 4 configurations, with varied timing and volume of saline flushes to refresh the dialysis compartment, then measured blood urea nitrogen (BUN) and potassium concentrations every 5 cycles. For each UF cycle, 1 ml of ultrafiltrate was removed, and Hct was measured every 10 cycles. Results: Median BUN and potassium reduction were 31.0% (interquartile range [IQR]: 17.6-37.9) and 35.0% (IQR: 26.9-41.7), respectively, after 30 clearance cycles. Median Hct increased to 52.6% (IQR: 52.5- 53.8) after 60 UF cycles, more than the expected Hct (47.7%). Conclusion: The Brophy Kit performs in vitro clearance efficiently and UF consistently. The Brophy Kit may address a technological KRT gap for small neonates because of its minimal extracorporeal volume and ability to function with single lumen access.

Acute kidney injury in children is associated with adverse outcomes. These include longer hospital stays, increased mortality, and nonrecovery of kidney function in the short term and increased health care utilization, new onset hypertension, and chronic kidney disease in the long term. Systematic post acute kidney injury care may help mitigate some of the complications that follow acute kidney injury. Patient, family, and health care team education is a key aspect of post acute kidney injury care. This includes individualized education to the patient and family, ideally prior to hospital discharge, provision of a discharge summary with details of the acute kidney injury episode and follow-up plan, and communication with the primary care provider. Given that severe acute kidney injury may often be seen in patients with other underlying medical conditions, partnership between the primary care provider, non-nephrology specialist and the nephrologist, and the use of telehealth may facilitate follow-up without increasing caregiver burden. Ongoing surveillance includes monitoring kidney function, proteinuria, and hypertension. There are no guidelines on the frequency of this evaluation or the duration of follow-up. These decisions should be individualized based on the characteristics of the index acute kidney injury episode and underlying risk factors for chronic kidney disease.

Key PointsTransdermal fluorescence detection of GFR measurement at the point of care with the fluorescent GFR tracer agent relmapirazin was evaluated.Measurement over the entire range of clinically meaningful GFR and the entire range of human skin tones was demonstrated.A linear regression of transdermally derived GFR to plasma-derived GFR yielded an r2 of 0.90 and P30 of 91.9%.BackgroundThe well-known accuracy limitations of eGFR currently used in clinical practice present barriers to optimal care for patients with, or at risk of, decreased kidney function. A point-of-care GFR measurement methodology has the potential to address these limitations. We prospectively assessed transdermal detection of the novel fluorescent GFR tracer agent relmapirazin in participants having normal or impaired kidney function across all human skin colors on the Fitzpatrick Skin Scale (FSS).MethodsA multicenter study comprising 74 participants with eGFR from normal to stage 4 CKD was performed. Forty-six participants were FSS types 1-3, and 28 were FSS types 4-6. A module containing a light-emitting diode and photodetector to activate and collect transdermal relmapirazin fluorescence was attached adhesively to the upper chest of each participant. Relmapirazin (1.5 mg/kg) was administered by intravenous push, and fluorescence emission was acquired for 12 hours. A two-compartment pharmacokinetic model fit the fluorescent intensity versus time data, and fluorescence clearance rate (FCR) was extracted from the second (terminal) compartment. Plasma relmapirazin concentrations were measured contemporaneously, and the corresponding plasma GFR for each participant was determined. Linear regression analysis was used to compare the FCR with the indexed plasma GFR.ResultsParticipant age range was 23-80 years, with 59% female. The two-compartment pharmacokinetic behavior was observed in the fluorescence intensity versus time data, and a FCR was successfully deduced for every participant completing the 12-hour study. The FCR versus indexed plasma GFR yielded an excellent correlation over the range of GFR measured and for all skin colors with a r2 of 0.90 (95% confidence interval, 0.85 to 0.94). No severe adverse events were reported.ConclusionsPoint-of-care transdermal detection of the fluorescent GFR tracer agent relmapirazin was feasible in patients with normal to impaired kidney function and for a range of skin color types.Clinical Trial registry name and registration number:ClinicalTrials.gov, NCT02772276.