Prognostic and Predictive Value of Endothelial Dysfunction Biomarkers in Sepsis-Associated Acute Kidney Injury: Risk Stratified Analysis from a Prospective Observational Cohort of Pediatric Septic Shock

Background Sepsis Associated Acute Kidney Injury (SA-AKI) is associated with high morbidity, with no current therapies available beyond continuous renal replacement therapy (CRRT). Systemic inflammation and endothelial dysfunction are key drivers of SA-AKI. We sought to measure differences between endothelial dysfunction markers among children with and without SA-AKI, test whether this association varied across inflammatory biomarker-based mortality risk strata and develop prediction models to identify those at highest risk of SA-AKI. Methods Secondary analyses of prospective observational cohort of pediatric septic shock. Primary outcome of interest was presence ≥ Stage II KDIGO SA-AKI on day 3 (D3 SA-AKI). Biomarkers including those prospectively validated to predict pediatric sepsis mortality (PERSEVERE-II) were measured in Day 1 (D1) serum. Multivariable regression was used to test the independent association between endothelial markers and D3 SA-AKI. We conducted risk-stratified analyses and developed prediction models using Classification and Regression Tree (CART), to estimate risk of D3 SA-AKI and prespecified subgroups based on PERSEVERE-II risk. Results 414 patients were included in the derivation cohort. Patients with D3 SA-AKI had worse clinical outcomes including 28-day mortality and need for CRRT. Serum soluble thrombomodulin (sTM), Angiopoietin-2 (Angpt-2), and Tie-2 were independently associated with D3 SA-AKI. Further, Tie-2 and Angpt-2/Tie-2 ratios were influenced by the interaction between D3 SA-AKI and mortality risk strata. Logistic regression demonstrated models predictive of D3 SA-AKI risk performed optimally among patients with high- or intermediate- PERSEVERE-II mortality risk strata. A 6 terminal node CART model restricted to this subgroup of patients had an area under the receiver operating characteristic curve (AUROC) 0.90 and 0.77 upon 10-fold cross-validation in the derivation cohort to distinguish those with and without D3 SA-AKI and high specificity. The newly derived model performed well in a unique set of patients (n = 224), 84 of whom were deemed high- or intermediate- PERSEVERE-II risk, to distinguish those patients with high vs. low risk of D3 SA-AKI. Conclusions Endothelial dysfunction biomarkers are independently associated with risk of severe SA-AKI. Pending validation, incorporation of endothelial biomarkers may facilitate prognostic and predictive enrichment for selection of therapeutics in future clinical trials among critically ill children.