David T. Selewski

The impact of disrupted fluid balance on outcomes in critically unwell children and adults is well described. Recent literature in neonates has demonstrated that both fluid overload and excessive postnatal fluid losses are associated with increased morbidity and mortality. However, neonates present unique challenges in measuring fluid balance as well as defining, preventing and treating fluid overload due to developmental changes in renal physiology, high trans‐epidermal losses, nutritional requirements and limitations in available renal replacement therapies. In the neonatal intensive care unit, significant variations exist in renal physiology and expected fluid shifts between neonates of differing gestational and chronological ages, as well as in the neonate's underlying co‐morbidities. As such, approaches to fluid balance should be individualised to each patient. Recognition of fluid balance as a vital sign, with implications as relevant as a patient's cardiorespiratory status, provides an important opportunity to improve outcomes. In this scoping review we discuss neonatal renal and fluid balance physiology, and present contemporary best practice strategies for measuring fluid balance. We explore the currently available prevention and treatment options for fluid overload in Australia and New Zealand as well as technological advances in neonatally‐adapted haemodialysis (HD) and continuous renal replacement therapies emerging internationally.

Background The prospective pediatric Continuous Renal Replacement Therapy (ppCRRT) registry identified the degree of fluid accumulation (FA) at continuous kidney replacement therapy (CKRT) initiation as a predictor of adverse outcomes in children. These predate major advancements in CKRT technology and fluid stewardship. We aimed to describe the epidemiology of FA at CKRT initiation and associated outcomes in a contemporary paediatric cohort. Methods Secondary analysis of Worldwide Exploration of Renal Replacement Outcomes Collaborative in Kidney Disease (WE-ROCK), a retrospective, multicenter study (35 centers, 9 countries) of patients ≤ 25 years treated with CKRT from 2015 to 2021. Primary Outcome: survival to ICU discharge. Secondary outcomes: ventilator-free and ICU-free days. Results A total of 1027 patients were included in this analysis. Survival to ICU discharge was 64.5% (n = 663). Median FA at CKRT initiation was 7.4% (IQR 2.4–18.1). FA differed between ICU survivors and non-survivors (7% [IQR 2–17] vs. 9% [IQR 3–21], p = 0.004). At CKRT initiation, 605 patients (58.9%) had FA < 10%, 194 patients (18.9%) had 10%–20% FA, and 228 patients (22.2%) had > 20% FA. In multivariable analysis, FA at CKRT initiation was not associated with ICU mortality but was associated with fewer ventilator (aOR 0.84, 95%CI 0.76–0.94, p = 0.023) and ICU-free days (aOR 0.6, 95%CI 0.49–0.73, p < 0.001). Conclusions The current study provides a contemporary evaluation of the epidemiology and impact of FA at CKRT initiation on outcomes in a cohort of > 1000 children treated with CKRT for FA/AKI. Clinically significant FA remains common at CKRT initiation and is associated with outcomes. This contemporary data can be used to inform clinical care and plan prospective studies. Graphical abstract The alternative text for this image may have been generated using AI. A higher resolution version of the Graphical abstract is available as Supplementary information

Background A 2017 international survey of neonatologist and pediatric nephrologist (PN) perceptions and practice showed that neonatal acute kidney injury (AKI) was underappreciated, and diagnosis and management varied significantly across centers. An updated survey was developed to determine whether perceptions and practices among international pediatric subspecialists have changed with increased awareness of AKI. Methods A 50-question electronic survey of AKI detection, monitoring, and follow-up was distributed to neonatologists, PNs, pediatric intensivists, and advanced practice providers (APPs) via 11 professional organizations (mid-March to mid-May 2024). Responses were compared by subspecialty and economic classification of respondents’ countries. Results Respondents totaled 676 (44.4% neonatologists, 38.3% PNs, 12.0% APPs, < 1.0% pediatric intensivists) representing 68 countries (36.7% high-income, 32.3% upper-middle income, 23.5% lower-middle income, 5.9% low-income, and 1.5% with unclassified economy). The modified, neonatal KDIGO criteria were most frequently used overall (46.1%) to diagnose AKI; however, only 30.7% of neonatologists and 14.8% of APPs utilized KDIGO. Most respondents reported no AKI identification (75.8%) nor monitoring protocol (75%). However, we identified higher rates of reported creatinine surveillance around aminoglycoside (72.9%) and indomethacin use (61.9%) than previously reported (34–36% and 24–62%, respectively) and improved creatinine access via a routine electrolyte panel (> 80% vs. 25–40% in the original survey). PN’s availability increased from 75% to > 80%. Conclusions Neonatal AKI perceptions and practices continue to vary across subspecialities, though improvements in access to serum creatinine monitoring and nephrology consultation are noted. Standardized approaches for AKI detection, management, and follow-up remain lacking indicating opportunities to improve care through provider education and guideline development. Graphical abstract A higher resolution version of the Graphical abstract is available as Supplementary information

Objective Racial and ethnic disparities in neonatal postoperative outcomes are reported, but differences in cardiac surgery-associated acute kidney injury (CS-AKI) remain unexamined. We assessed racial/ethnic disparities in CS-AKI prevalence and outcomes in neonates undergoing congenital heart surgery. Design, Setting, and Patients Retrospective cohort of neonates across 22 centers (2015–2018) from the Pediatric Cardiac Critical Care Consortium and the Neonatal and Pediatric Heart and Renal Outcomes Network. Measurements Race/ethnicity (primary predictor) were categorized into eight groups; CS-AKI was defined using neonatal modified Kidney Disease: Improving Global Outcomes criteria as mild (stage 1), severe (≥ stage 2) and persistent (any stage beyond post-operative day [POD] 3). Outcomes included not achieving net negative fluid balance [FB], respiratory support duration, length of stay [LOS], and mortality. Multivariable regression models examining the association between race/ethnicity and outcomes were also constructed. Results Among 2,165 neonates (2% Asian, 18% Hispanic, 1% multi-racial, 0.3% Native American, 14% Non-Hispanic Black (NHB), 59% Non-Hispanic White (NHW), 5% other, and 0.2% Pacific Islander), CS-AKI prevalence (31% mild, 23% severe) did not differ across racial/ethnic groups. NHB neonates had lower birthweight and higher surgical complexity, while NHW neonates had higher private insurance rates. NHB neonates were less likely to not achieve a net negative FB until ≥ POD3 than NHW neonates, but no differences were found in respiratory support duration, hospital LOS, or mortality after multivariate adjustment. Non-white neonates with severe AKI had higher mortality but had similar clinical outcomes. Conclusions CS-AKI rates did not vary by race/ethnicity. Differences in fluid balance achievement were noted but no significant disparities were found in mortality, mechanical ventilation duration, or hospital LOS.

Impact The consensus neonatal modified KDIGO definition has been crucial in expanding our understanding of the epidemiology and impact of neonatal AKI. A consensus definition of neonatal AKI remains essential to continuing to advance the field. This manuscript highlights a historical perspective, the strengths, and limitations of the current neonatal AKI definition, and reflects on the optimal characteristics and utility of neonatal AKI definitions. The future of neonatal AKI lies with improved diagnostic precision and consistently incorporating neonatal risk factors into risk stratification incorporating and the deployment of novel biomarkers to aid in earlier identification and improve outcomes in neonatal AKI.

Introduction: Nephrotic syndrome (NS), a common glomerular disease in children, is classified based on response to corticosteroid therapy as either steroid-sensitive nephrotic syndrome (SSNS), or steroid-resistant nephrotic syndrome (SRNS). However, there are currently no reliable predictors of therapy response at initial clinical presentation. Methods: We conducted genome-wide association studies, developed polygenic risk scores (PRS) for therapy response and analyzed classical HLA alleles in 1,997 (994 discovery and 1,003 replication/validation cohorts) previously unstudied children with NS and 3,558 ancestry-matched controls. Results: A significant association with HLA loci defined by variants in HLA-DQB1, HLA-DRB1 , and HLA-DQA1 were found for SSNS (but not SRNS), along with a second immune-related SSNS locus: CLEC16A . A PRS that discriminates between SSNS and SRNS was validated in two independent cohorts. The HLA haplotype HLA-DRB1*07:01∼DQA1*02:01∼DQB1*02:02 was associated with ∼4 times the risk of developing SSNS. A model incorporating HLA haplotype, PRS score, and age at onset of the disease was the best predictor of steroid responsiveness with an AUC of 0.68-0.70 and an overall classification accuracy of SSNS versus SRNS of 67-71%. Conclusions: Our findings confirm that SSNS (unlike SRNS) is an immune-mediated HLA-associated disorder. The PRS for therapy response and HLA haplotype can serve as biomarkers and provide a foundation for more accurate diagnoses and tailored and individualized treatment. Translational statement: To identify biomarkers of pattern of steroid responsiveness in childhood-onset nephrotic syndrome, we carried out a case-control study that included over 4,000 samples, including 994 patients with NS in the discovery phase and an additional 1,003 cases from two independent replication cohorts. We identified significant risk of steroid-sensitive NS (SSNS) at HLA class II genes and CLEC16A (a gene important in the regulation of T and B lymphocytes). The HLA haplotype DRB1*07:01∼DQA1*02:01∼DQB1*02:02 was associated with four-fold increased odds of SSNS. A model incorporating HLA haplotype, polygenic risk score, and age at onset of the disease was the best predictor of steroid responsiveness providing useful delineation of steroid sensitivity from steroid resistance. In conclusion, age at onset of disease, HLA class II variants and polygenic risk scores are useful biomarkers of corticosteroid response in childhood NS and may serve as useful clinical decision support tools to guide treatment. Abstract Figure: Graphical Abstract