Biomarkers of acute kidney injury in a prospective pediatric ECMO cohort

PROJECT SUMMARY The use of extracorporeal membrane oxygenation (ECMO), a technique of extracorporeal life support used for severe refractory cardiopulmonary failure or cardiac arrest, has more than doubled in children over the last 15 years. While lifesaving, ECMO is associated with high mortality and significant morbidity, with nearly two-third of children developing acute kidney injury (AKI) during the ECMO course. AKI is also associated with increased risk of mortality and morbidity at hospital discharge with unknown long-term kidney outcomes in survivors in the U.S. AKI in pediatric ECMO has multifactorial etiology and data to support evidence-based AKI prevention and management strategies are sparse and based primarily on retrospective reviews of electronic health records. Consequently, there is high variability in clinical practice across ECMO centers, and lack of consensus or clinical practice guidelines on optimal fluid, diuretic, and kidney replacement therapy (KRT) strategies in this patient population. The overall goal of this research is to develop and refine an AKI multimarker panel for accurate kidney function monitoring at the bedside and early classification of morbidity and mortality outcomes that will allow timely interventions to optimize kidney health. We hypothesize that early detection of AKI using novel blood- and urine-based biomarkers with careful implementation of fluid, diuretic, and KRT strategies, have the potential to improve kidney function and patient outcomes in the high-risk pediatric ECMO population. For this project, we propose the secondary use of data and biospecimens of a recently completed prospective multicenter cohort of children on ECMO enrolled between 2020 and 2023 (n=200 children). In this proposal, we aim to determine if urine and plasma biomarkers measured serially during ECMO can predict AKI and classify major adverse kidney events at hospital discharge (Aim 1), and whether prevention of fluid overload through early initiation of diuretic therapy or KRT while avoiding hypovolemia is associated with AKI biomarker trajectory and with major adverse kidney events at hospital discharge (Aim 2). Urine biomarkers include indicators of subclinical AKI (neutrophil gelatinase-associated lipocalin [NGAL]), of persistence of severe AKI (C–C motif chemokine ligand 14 [CCL14]), and prediction and diagnosis of AKI and assessment of severity (tissue inhibitor of metalloproteinases-2 [TIMP2] and insulin-like growth factor binding protein 7 [IGFBP-7]). Urine biomarker measurements will be normalized to urinary creatinine concentration. Plasma biomarkers include inflammatory markers interleukin 8 (IL-8) and tumor necrosis factor alpha (TNF-α). Preliminary results through the study proposed will allow refinement of the AKI biomarker panel and the development of novel risk models for short- and long-term kidney-related outcomes in the pediatric ECMO population. This in turn will allow for the design of future prospective clinical cohorts and interventional trials aiming to optimize multimodal kidney protective strategies during critical illness with ECMO support, and to investigate post-discharge interventions to improve long-term kidney function.