Plasma total fibroblast growth factor 23 levels are associated with acute kidney injury and mortality in children with acute respiratory distress syndrome

Abstract

Acute respiratory distress syndrome (ARDS) has high rates of mortality and multisystem morbidity. Pre-clinical data suggest that fibroblast growth factor 23 (FGF23) may contribute to pulmonary pathology, and FGF23 is associated with mortality and morbidity, including acute kidney injury (AKI), in non-ARDS cohorts. Here, we assess whether FGF23 is associated with AKI and/or mortality in a cohort of 161 pediatric ARDS patients. Plasma total (intact + C-terminal) FGF23 and intact FGF23 concentrations were measured within 24 hours of ARDS diagnosis (Day 1), and associations with Day 3 AKI and 60-day mortality were evaluated. 35 patients (22%) developed AKI by 3 days post-ARDS diagnosis, and 25 (16%) died by 60 days post-ARDS diagnosis. In unadjusted models, higher Day 1 total FGF23 was associated with Day 3 AKI (odds ratio (OR) 2.22 [95% confidence interval (CI) 1.62, 3.03], p<0.001), but Day 1 intact FGF23 was not. In a model adjusted for demographics and disease severity, total FGF23 remained associated with AKI (OR 1.52 [95% CI 1.02, 2.26], p = 0.039). In unadjusted models, both higher Day 1 total and intact FGF23 were associated with 60-day mortality (OR 1.43 [95% CI 1.07, 1.91], p = 0.014; and OR 1.44 [95% CI 1.02, 2.05], p = 0.039, respectively). In the adjusted model, only total FGF23 remained associated with 60-day mortality (OR 1.62 [95% CI 1.07, 2.45], p = 0.023). In a subgroup analysis of patients with Day 1 plasma IL-6 concentrations available, inflammation partially mediated the association between total FGF23 and AKI. Our data suggest both inflammation-dependent and inflammation-independent associations between total FGF23 and clinical outcomes in pediatric ARDS patients.

Pathobiology, Severity, and Risk Stratification of Pediatric Acute Respiratory Distress Syndrome: From the Second Pediatric Acute Lung Injury Consensus Conference

“…ARDS pathobiology is characterized by inflammation, loss of the alveolar epithelial, and lung vascular endothelial permeability barriers, dysregulated coagulation, and fibrosis. Recent advances related to individual and combinations of plasma biomarkers indicative of many of these aspects of PARDS pathobiology and studies aimed at identifying subphenotypes at greater risk of worse clinical outcome and/or response to therapy are described in the sections below (5, 22, 45, 49, 70, 96–139). Subphenotype identification offers enhanced prognostic ability beyond what bedside physiologic biomarkers and/or PARDS trigger (e.g., pneumonia, sepsis, trauma, etc.)…”

“…A multiple logistic regression model incorporating OI, IL-8, and TNFR2 was superior to a model of OI alone in predicting the composite outcome of mortality or severe morbidity (AUROC [95% CI], 0.77 [0.70–0.83] vs 0.70 [0.62–0.77]; p = 0.042) (108). In the same cohort of children, higher levels of total fibroblast growth factor 23 on day 1 of ARDS were associated with both acute kidney injury and mortality and mediation analysis suggested that this effect was likely partially mediated by inflammation (120). Interestingly, children in this cohort with a history of hematopoietic cellular transplantation (HCT) had higher levels of IL-8, IL-18, IL-10, and TNFR2 (108).…”

Assessing the value of serum and urinary interleukins for diagnosis of acute kidney injury in children and adolescents: A systematic review and meta-analysis

“…Search in databases resulted in 987 non-duplicate articles. After screening, 21 studies [ [20] , [21] , [22] , [23] , [24] , [25] , [26] , [27] , [28] , [29] , [30] , [31] , [32] , [33] , [34] , [35] , [36] , [37] , [38] , [39] , [40] ] were included in the current meta-analysis ( Fig. 1 ).…”

A review of ferric citrate clinical studies, and the rationale and design of the Ferric Citrate and Chronic Kidney Disease in Children (FIT4KiD) trial

“…For human samples, there are commercial assays to measure both C-terminal FGF23 and intact FGF23 [50]. The C-terminal assay captures both intact FGF23 and C-terminal FGF23 fragments, thus measuring total (intact + fragmented) FGF23 concentrations.…”