110 - Nephrotoxic Acute Kidney Injury Impairs Alveolar Development in Neonatal Rats

Poster Number: 110
Publication Number: 110.125

Brianna Liberio, Children's Hospital Colorado, Denver, CO, United States; Gregory J. Seedorf, University of Colorado School of Medicine, Aurora, CO, United States; Danielle E. Soranno, University of Colorado School of Medicine, Denver, CO, United States; John R. Montford, University of Colorado School of Medicine, Denver, CO, United States; Sarah Faubel, University of Colorado Anschutz Medical Campus, denver, CO, United States; Steven Abman, University of Colorado School of Medicine, denver, CO, United States; Jason Gien, University of Colorado School of Medicine, Englewood, CO, United States

Background: Acute kidney injury (AKI) is common in critically ill neonates and associated with adverse pulmonary outcomes. Nephrotoxic medications are frequently administered to critically ill neonates and are associated with increased risk of AKI. Adult literature demonstrates that AKI creates a systemic inflammatory state, resulting in acute lung injury. While prior studies in neonates have demonstrated a link between altered angiogenic signaling and lung injury, the mechanisms responsible for lung injury after neonatal AKI remain unknown.

Objective: To determine the effect of neonatal nephrotoxic AKI on lung structure and angiogenic signaling in rat pups.

Design/Methods: Like the preterm infant, Sprague-Dawley rat pups have incomplete lung and kidney development at birth. Rat pups underwent subcutaneous injections of aristolochic acid (AA), a known nephrotoxin, on day of life (DOL) 2 and 4. On DOL 6, AKI was confirmed with serum blood urea nitrogen (BUN), creatinine, and renal immunohistochemistry for KIM-1, a renal tubular injury biomarker. On DOL 14, lung morphometrics were assessed by radial alveolar counts (RAC), and angiogenic signaling was assessed by vascular endothelial growth factor (VEGF) protein expression in lung homogenates. Pulmonary vessel density was measured using lung immunohistochemistry for von Willebrand factor, a marker for endothelial cells.

Results: When compared to controls, AA-exposed pups demonstrated a 75% increase in BUN (p < 0.001) and positive KIM-1 staining on renal immunohistochemistry. In AA-exposed pups, RACs were reduced by 26% (p < 0.01) and VEGF protein expression was reduced by 84% (p < 0.0001) compared to controls. Pulmonary vessel density was reduced by 30% in AA-exposed pups compared to controls (p < 0.001).Conclusion(s): Nephrotoxic AKI in neonatal rat pups results in decreased alveolarization and pulmonary vessel density. We speculate that altered angiogenic signaling is responsible for arrested lung development.