Factors associated with successful liberation from continuous renal replacement therapy in children and young adults: analysis of the worldwide exploration of renal replacement outcomes collaborative in Kidney Disease Registry.

PURPOSE: Continuous renal replacement therapy (CRRT) is used for supportive management of acute kidney injury (AKI) and disorders of fluid balance (FB). Little is known about the predictors of successful liberation in children and young adults. We aimed to identify the factors associated with successful CRRT liberation. METHODS: The Worldwide Exploration of Renal Replacement Outcomes Collaborative in Kidney Disease study is an international multicenter retrospective study (32 centers, 7 nations) conducted from 2015 to 2021 in children and young adults (aged 0-25 years) treated with CRRT for AKI or FB disorders. Patients with previous dialysis dependence, tandem extracorporeal membrane oxygenation use, died within the first 72 h of CRRT initiation, and those who never had liberation attempted were excluded. Patients were categorized based on first liberation attempt: reinstituted (resumption of any dialysis within 72 h) vs. success (no receipt of dialysis for ≥ 72 h). Multivariable logistic regression was used to identify factors associated with successful CRRT liberation. RESULTS: A total of 622 patients were included: 287 (46%) had CRRT reinstituted and 335 (54%) were successfully liberated. After adjusting for sepsis at admission and illness severity parameters, several factors were associated with successful liberation, including higher VIS (vasoactive-inotropic score) at CRRT initiation (odds ratio [OR] 1.35 [1.12-1.63]), higher PELOD-2 (pediatric logistic organ dysfunction-2) score at CRRT initiation (OR 1.71 [1.24-2.35]), higher urine output prior to CRRT initiation (OR 1.15 [1.001-1.32]), and shorter CRRT duration (OR 0.19 [0.12-0.28]). CONCLUSIONS: Inability to liberate from CRRT was common in this multinational retrospective study. Modifiable and non-modifiable factors were associated with successful liberation. These results may inform the design of future clinical trials to optimize likelihood of CRRT liberation success.

Major Adverse Kidney Events in Pediatric Continuous Kidney Replacement Therapy.

Importance: Continuous kidney replacement therapy (CKRT) is increasingly used in youths with critical illness, but little is known about longer-term outcomes, such as persistent kidney dysfunction, continued need for dialysis, or death. Objective: To characterize the incidence and risk factors, including liberation patterns, associated with major adverse kidney events 90 days after CKRT initiation (MAKE-90) in children, adolescents, and young adults. Design, Setting, and Participants: This international, multicenter cohort study was conducted among patients aged 0 to 25 years from The Worldwide Exploration of Renal Replacement Outcomes Collaborative in Kidney Disease (WE-ROCK) registry treated with CKRT for acute kidney injury or fluid overload from 2015 to 2021. Exclusion criteria were dialysis dependence, concurrent extracorporeal membrane oxygenation use, or receipt of CKRT for a different indication. Data were analyzed from May 2 to December 14, 2023. Exposure: Patient clinical characteristics and CKRT parameters were assessed. CKRT liberation was classified as successful, reinstituted, or not attempted. Successful liberation was defined as the first attempt at CKRT liberation resulting in 72 hours or more without return to dialysis within 28 days of CKRT initiation. Main Outcomes and Measures: MAKE-90, including death or persistent kidney dysfunction (dialysis dependence or ≥25% decline in estimated glomerular filtration rate from baseline), were assessed. Results: Among 969 patients treated with CKRT (529 males [54.6%]; median [IQR] age, 8.8 [1.7-15.0] years), 630 patients (65.0%) developed MAKE-90. On multivariable analysis, cardiac comorbidity (adjusted odds ratio [aOR], 1.60; 95% CI, 1.08-2.37), longer duration of intensive care unit admission before CKRT initiation (aOR for 6 days vs 1 day, 1.07; 95% CI, 1.02-1.13), and liberation pattern were associated with MAKE-90. In this analysis, patients who successfully liberated from CKRT within 28 days had lower odds of MAKE-90 compared with patients in whom liberation was attempted and failed (aOR, 0.32; 95% CI, 0.22-0.48) and patients without a liberation attempt (aOR, 0.02; 95% CI, 0.01-0.04). Conclusions and Relevance: In this study, MAKE-90 occurred in almost two-thirds of the population and patient-level risk factors associated with MAKE-90 included cardiac comorbidity, time to CKRT initiation, and liberation patterns. These findings highlight the high incidence of adverse outcomes in this population and suggest that future prospective studies are needed to better understand liberation patterns and practices.

Concentration of novel urinary tract infection biomarkers in neonates.

Urinary tract infections (UTIs) are a common comorbidity in hospitalized neonates. The current UTI diagnostics have several limitations including invasive collection of urinary samples to ensure sterility, risk of contamination and lack of consensus definitions of UTI based on urine culture. Antimicrobial peptides (AMPs) have been recently utilized as novel biomarkers that can efficiently and accurately diagnose pediatric UTI. However, the concentration of AMPs in neonatal urine is not well-defined. Urine from neonates admitted to a single level IV neonatal intensive care unit was obtained to determine baseline concentration of two AMPs, Ribonuclease 7 (RNase 7) and Beta Defensin-1 (BD-1) and to define the relationship between AMP concentration and gestational age (GA). AMP levels were normalized to urine creatinine. RNase 7 and BD-1 were expressed in neonatal urine (n = 66) regardless of GA and as early as 22 weeks gestation. Urinary concentrations of both AMPs decreased as GA and birthweight increased. The overall median urinary RNase 7/UCr and BD-1/UCr values were 271 ng/mg, and 116 ng/mg, respectively. Median urinary concentrations of RNase 7/UCr for infants born at < 27, 27-32, 33-35 and ≥ 36 weeks were 569, 308, 254, and 124 ng/mg respectively. Similarly, the concentrations of BD-1/UCr at these GA were 166, 115, 108, and 14 ng/mg, respectively. Baseline neonatal urinary concentration of two AMPs (RNase 7 and BD-1) and the variation by GA were identified. This is an essential first step toward the potential utilization of AMPs in improving neonatal UTI diagnostics.

Understanding Similarities and Differences in CKD and Dialysis Care in Children and Adults.

In lower-income settings there is often a dearth of resources and nephrologists, especially pediatric nephrologists, and individual physicians often find themselves caring for patients with chronic kidney diseases and end-stage kidney failure across the age spectrum. The management of such patients in high-income settings is relatively protocolized and permits high-volume services to run efficiently. The basic principles of managing chronic kidney disease and providing dialysis are similar for adults and children, however, given the differences in body size, causes of kidney failure, nutrition, and growth between children and adults with kidney diseases, nephrologists must understand the relevance of these differences, and have an approach to providing quality and safe dialysis to each group. Prevention, early diagnosis, and early intervention with simple therapeutic and lifestyle interventions are achievable goals to manage symptoms, complications, and reduce progression, or avoid kidney failure in children and adults. These strategies currently are easier to implement in higher-resource settings with robust health systems. In many low-resource settings, kidney diseases are only first diagnosed at end stage, and resources to pay out of pocket for appropriate care are lacking. Many barriers therefore exist in these settings, where specialist nephrology personnel may be least accessible. To improve management of patients at all ages, we highlight differences and similarities, and provide practical guidance on the management of children and adults with chronic kidney disease and kidney failure. It is important that children are managed with a view to optimizing growth and well-being and maximizing future options (eg, maintaining vein health and optimizing cardiovascular risk), and that adults are managed with attention paid to quality of life and optimization of physical health.

Perioperative Neonatal Acute Kidney Injury Is Common: Risk Factors for Poor Outcomes.

OBJECTIVE: Perioperative acute kidney injury (AKI) is associated with poor patient outcomes. The epidemiology of perioperative AKI is characterized in children and to a lesser extent in neonates with cardiac disease. We hypothesized that the prevalence of noncardiac perioperative AKI in neonates is higher than in older children. We also hypothesized that certain neonatal characteristics and comorbidities increase the risk of perioperative AKI and hospital mortality. We aimed to characterize the epidemiology and risk factors of perioperative AKI in neonates undergoing noncardiac surgeries and outline the associated mortality risk factors. STUDY DESIGN: We performed a retrospective study of neonates ≤28 days old who underwent inpatient noncardiac surgery in 46 U.S. children's hospitals participating in the Pediatric Hospital Information System between 2016 and 2021. AKI was evaluated throughout the surgical admission encounter. AKI was defined using the International Classification of Diseases (ICD) versions 9 and 10 codes. Comorbid risk factors are chronic and longstanding diagnoses and were selected using ICD-9 and ICD-10 diagnostic and procedure codes. RESULTS: Perioperative AKI occurred in 10% of neonates undergoing noncardiac surgeries. Comorbidities associated with high risk of perioperative AKI included metabolic, hematologic/immunologic, cardiovascular, and renal disorders. The relative risk of mortality in perioperative AKI was highest in infants with low birthweight (relative risk = 1.49, 1.14-1.94) and those with hematologic (1.46, 1.12-1.90), renal (1.24, 1.01-1.52), and respiratory comorbidities (1.35, 1.09-1.67). CONCLUSION: Perioperative AKI is common in neonates undergoing noncardiac surgeries. Infants with high-risk comorbidity profiles for the development of perioperative AKI and mortality may benefit from close surveillance of their kidney function in the perioperative period. Although retrospective, the findings of our study could inform clinicians to tailor neonatal perioperative kidney care to improve short- and long-term outcomes. KEY POINTS: · AKI is common in neonates undergoing noncardiac surgeries.. · Extremely preterm and very low birth weight neonates have the highest rates of perioperative AKI.. · Renal, hematologic, and respiratory comorbidities increase mortality risk in neonates with perioperative AKI..

Positive fluid balance and diuretic therapy are associated with mechanical ventilation and mortality in preterm neonates in the first fourteen postnatal days.

BACKGROUND: Fluid overload leads to poor neonatal outcomes. Diuretics may lower the rates of mechanical ventilation (MV) and mortality in neonates with fluid overload. METHODS: This is a retrospective study of preterm neonates ≤ 36 weeks of gestational age (GA) in the first 14 postnatal days in a level IV NICU in 2014-2020. We evaluated the epidemiology of fluid balance in the first 14 postnatal days and its association with MV and mortality and studied the association of diuretics with fluid balance, MV, and mortality. RESULTS: In 1383 included neonates, the overall median lowest and peak fluid balances were - 7.8% (IQR: - 11.7, - 4.6) and 8% (3, 16) on days 3 (2, 5) and 13 (5, 14), respectively. Fluid balance distribution varied significantly by GA. Peak fluid balance of ≥ 10% was associated with increased odds of MV on days 7 and 14 with highest odds ratios (OR) of MV in neonates with fluid balance ≥ 15%. Peak fluid balance of ≥ 15% was associated with the greatest odds of mortality. Diuretics were used more frequently in neonates with younger GA, smaller birthweight, positive fluid balance, and those on MV. CONCLUSIONS: Positive fluid balance negatively impacts pulmonary status. The odds of MV and death increase significantly as peak fluid balance percentage increases in all GA groups. The impact of diuretics on MV and death in preterm neonates needs further evaluation. A higher resolution version of the Graphical abstract is available as Supplementary information.

Kidney support for babies: building a comprehensive and integrated neonatal kidney support therapy program.

Kidney support therapy (KST), previously referred to as Renal Replacement Therapy, is utilized to treat children and adults with severe acute kidney injury (AKI), fluid overload, inborn errors of metabolism, and kidney failure. Several forms of KST are available including peritoneal dialysis (PD), intermittent hemodialysis (iHD), and continuous kidney support therapy (CKST). Traditionally, extracorporeal KST (CKST and iHD) in neonates has had unique challenges related to small patient size, lack of neonatal-specific devices, and risk of hemodynamic instability due to large extracorporeal circuit volume relative to patient total blood volume. Thus, PD has been the most commonly used modality in infants, followed by CKST and iHD. In recent years, CKST machines designed for small children and novel filters with smaller extracorporeal circuit volumes have emerged and are being used in many centers to provide neonatal KST for toxin removal and to achieve fluid and electrolyte homeostasis, increasing the options available for this unique and vulnerable group. These new treatment options create a dramatic paradigm shift with recalibration of the benefit: risk equation. Renewed focus on the infrastructure required to deliver neonatal KST safely and effectively is essential, especially in programs/units that do not traditionally provide KST to neonates. Building and implementing a neonatal KST program requires an expert multidisciplinary team with strong institutional support. In this review, we first describe the available neonatal KST modalities including newer neonatal and infant-specific platforms. Then, we describe the steps needed to develop and sustain a neonatal KST team, including recommendations for provider and nursing staff training. Finally, we describe how quality improvement initiatives can be integrated into programs.

Describing patterns in serum creatinine in infants with and without necrotizing enterocolitis.

OBJECTIVE: To evaluate serum creatinine (SCr) patterns and the development of acute kidney injury (AKI), as potential biomarkers of necrotizing enterocolitis (NEC). STUDY DESIGN: Retrospective chart review of preterm infants with and without NEC born 23-32 weeks gestation admitted to Nationwide Children's Hospital NICU. Medical versus surgical NEC was determined by radiographic and clinical findings. Available inpatient SCr levels obtained on days 8 through 365 were included. RESULT: In this cohort, 77 NEC and a randomly selected group of 82 non-NEC infants met inclusion criteria. Fifteen of the 70 (21.4%) with NEC met criteria for AKI versus 0 of 43 (0.0%) without NEC. One of the 13 with AKI had AKI within 7 days prior to NEC diagnosis (7.7%). CONCLUSION: AKI is more prevalent in infants with NEC. The temporal association between AKI and NEC could not be evaluated due to inconsistent SCr surveillance and should be evaluated in future studies.

Nephrotoxic medications and associated acute kidney injury in hospitalized neonates.

OBJECTIVES: Hospitalized neonates are often treated with nephrotoxic medications, a known risk factor for acute kidney injury (AKI). Nephrotoxic medications and AKI, especially in periviable neonates, could be detrimental to nephrogenesis. Our objectives were to evaluate the prevalence of neonatal treatment with nephrotoxic medications and its relationship with AKI in in the first 28 days of life, and to delineate the associated demographics and diagnoses. STUDY DESIGN: Multicenter retrospective analysis using the national Pediatric Hospital Information System database, including 49 pediatric hospitals. Neonates admitted within the first two postnatal days were included. Treatment with 37 nephrotoxic medications across demographics and clinical variables, and relationship with AKI were evaluated. AKI was determined by using the International Classification of Diseases codes. RESULTS: Of 192,229 neonates, 74% were treated with at least one nephrotoxic medication. Incidence of AKI was significantly higher in the treated group (aRR 3.68 [95% CI: 2.85, 4.75]). The aRRs of treatment were increased in infants born < 32-week, and < 2000 g. Nephrotoxic medications were prescribed to 90-95% of neonates born ≤ 28-week gestational age. Most treatments (95-98%) occurred in the first 3 days. Intravascular aminoglycosides were the most frequent type; 28% of neonates were treated for ≥ 4 calendar days. Most common diagnoses were infections (25%) and patent ductus arteriosus (20%). CONCLUSIONS: Neonatal treatment with nephrotoxic medications is common, especially among the smallest, most immature preterm neonates and demonstrates a need for initiatives to reduce neonatal exposure to these agents, when feasible. Across all gestational age categories, the prevalence of AKI is higher in the neonates treated with nephrotoxic drugs. The long-term effects of treatment with nephrotoxic medications and subsequent AKI on nephrogenesis and nephron endowment will need to be evaluated.

Improving the identification of acute kidney injury in the neonatal ICU: three centers' experiences.

OBJECTIVE: To describe three different standardized approaches to improving neonatal acute kidney injury (AKI) identification and the impact on AKI identification, incidence, and nephrology consultation and referral. STUDY DESIGN: A retrospective cohort study in three academic NICUs. We compared AKI identification, AKI incidence, nephrology consultation, and nephrology follow-up before and after implantation of local protocols to standardize neonatal AKI identification. RESULT: Neonatal AKI identification improved in all three NICUs following protocol implementation (26-85%, P < 0.0001). Each center also saw increases in nephrology consultation (15-83%, P < 0.0001) and nephrology follow-up (7-73%, P < 0.0001). AKI incidence decreased significantly (21-12%, P < 0.0001). CONCLUSION: Multiple strategies can be successfully operationalized to improve neonatal AKI identification. While different in approach, each strategy resulted in increased AKI identification and nephrology involvement. This study emphasizes the importance of local standardized approaches to AKI to improve AKI identification and nephrology involvement in the NICU.

Diuretic therapy and acute kidney injury in preterm neonates and infants.

BACKGROUND: Acute kidney injury (AKI) in preterm infants is associated with prolonged hospitalization and high mortality. Diuretic therapy has been used to enhance urine output in preterm infants with AKI. Treatment with diuretics, prescription patterns, and relationship with length of stay (LOS), mechanical ventilation (MV), and mortality in preterm infants who also had AKI have not been fully evaluated. METHODS: This multicenter retrospective study used the Pediatric Hospital Information System database. We included 2121 preterm infants with AKI diagnosis from 46 hospital Neonatal Intensive Care Units (NICUs) born <37 weeks gestational age (GA). Treatment with diuretics, practice patterns across 46 NICUs in the USA, and associated outcomes including LOS, MV, and mortality were evaluated. RESULTS: Seventy-six percent of infants received at least one dose of diuretics (median treatment 18 days). Diuretic prescription varied significantly across hospitals and ranged from 42 to 96%. Diuretics were used more frequently in infants with younger GA and smaller birth weight. Infants with older GA who received diuretics at or before 28 days postnatally had worse survival even after adjusting for known confounders. CONCLUSIONS: Preterm infants with AKI diagnosis were frequently treated with diuretics. Moreover, infants with younger GA and smaller birth weight were more likely to receive diuretics. Worse survival in infants with older GA who received diuretics could be the result of more underlying severe illness in these infants and not the cause of more severe illness. Prospective studies are needed to best determine patient safety and outcomes with diuretic treatment in preterm infants with AKI. A higher resolution version of the Graphical abstract is available as Supplementary information.

Prophylactic Indomethacin in extremely preterm infants: association with death or BPD and observed early serum creatinine levels.

OBJECTIVES: To identify the relationship between prophylactic indomethacin (PI) administration and (1) mortality and bronchopulmonary dysplasia (BPD) at 36-week postmenstrual age (PMA) (primary outcome), and (2) to evaluate for PI-associated acute kidney injury. STUDY DESIGN: Retrospective cohort investigation of 22-28 weeks gestation infants (N = 1167) who were admitted to Nationwide Children's Hospital on postnatal days 0-1 between May 2009 and September 2017 and survived ≥24-h postnatal. The associations of PI treatment with mortality or BPD, and other secondary outcomes, were evaluated via multivariable robust-error-variance Poisson regression. RESULTS: The adjusted risks of death or BPD (1.02, 95% CI: 0.83, 1.25), BPD (0.97, 95% CI: 0.77, 1.21), and death 1.33 (95% CI: 0.84, 2.10) by 36-week PMA were unchanged following PI treatment after multivariable adjustment. No changes in mean creatinine levels were detected in exposed versus unexposed infants to suggest PI-induced AKI. CONCLUSION: Prophylactic indomethacin treatment was unrelated to mortality or BPD outcomes.

Renin-Expressing Cells Require ß1-Integrin for Survival and for Development and Maintenance of the Renal Vasculature.

Juxtaglomerular cells are crucial for blood pressure and fluid-electrolyte homeostasis. The factors that maintain the life of renin cells are unknown. In vivo, renin cells receive constant cell-to-cell, mechanical, and neurohumoral stimulation that maintain their identity and function. Whether the presence of this niche is crucial for the vitality of the juxtaglomerular cells is unknown. Integrins are the largest family of cell adhesion molecules that mediate cell-to-cell and cell-to-matrix interactions. Of those, ß1-integrin is the most abundant in juxtaglomerular cells. However, its role in renin cell identity and function has not been ascertained. To test the hypothesis that cell-matrix interactions are fundamental not only to maintain the identity and function of juxtaglomerular cells but also to keep them alive, we deleted ß1-integrin in vivo in cells of the renin lineage. In mutant mice, renin cells died by apoptosis, resulting in decreased circulating renin, hypotension, severe renal-vascular abnormalities, and renal failure. Results indicate that cell-to-cell and cell-to-matrix interactions via ß1-integrin is essential for juxtaglomerular cells survival, suggesting that the juxtaglomerular niche is crucial not only for the tight regulation of renin release but also for juxtaglomerular cell survival-a sine qua non condition to maintain homeostasis.

Development of the renal vasculature.

The kidney vasculature has a unique and complex architecture that is central for the kidney to exert its multiple and essential physiological functions with the ultimate goal of maintaining homeostasis. An appropriate development and coordinated assembly of the different vascular cell types and their association with the corresponding nephrons is crucial for the generation of a functioning kidney. In this review we provide an overview of the renal vascular anatomy, histology, and current knowledge of the embryological origin and molecular pathways involved in its development. Understanding the cellular and molecular mechanisms involved in renal vascular development is the first step to advance the field of regenerative medicine.