Acute Kidney Injury in Neonates Imitates Bronchopulmonary Dysplasia

Research study background

Acute kidney injury (AKI) poses a serious risk to neonates, especially those born prematurely. AKI is associated with a longer hospital length of stay, poor pulmonary outcomes including bronchopulmonary dysplasia (BPD), the need for mechanical ventilation or oxygen and a higher risk of death. A recent study found that 30% of neonates admitted to neonatal intensive care units will experience AKI, where they may be exposed to additional AKI risk factors such as nephrotoxic medications and surgical interventions. The mechanisms responsible for these poor outcomes are unknown and, until now, it has been challenging to perform translational research in this area due to the lack of preclinical animal models.

In this study, reported in the Nature journal Pediatric Research, experts from Neonatology and the Breathing Institute at Children’s Hospital Colorado collaborated with investigators from the University of Colorado School of Medicine, Indiana University Riley Children’s Hospital, and Cincinnati Children’s Hospital. The multidisciplinary team developed novel models to explore the systematic short- and long-term effects of AKI on lung development in neonates.

AKI was induced in rat pups either pharmacologically using aristolochic acid (AA) or surgically using bilateral ischemia-reperfusion injury (bIRI). Surgical models were compared to non-surgical models and sham models, while pharmacologic models were compared to vehicle controls. While surprising, their finding was consistent with what is seen clinically: Infants that undergo surgery in the NICU have more severe BPD and worse pulmonary outcomes.

Both AA and bIRI models of AKI demonstrated decreased alveolarization (the final stage of lung development that shapes its internal surface area for gas exchange) and angiogenesis (the development of new blood vessels). Surgical sham models did not experience AKI, but they did exhibit the unexpected finding of decreased alveolarization and angiogenesis compared to controls.

Study authors concluded that pharmacologic AKI and surgery in neonatal rat pups, with or without AKI, decreased alveolarization and angiogenesis, producing a pulmonary effect that mimics BPD. This is the first preclinical study of neonates confirming the association between AKI and lung injury, which explains why neonates with AKI experience adverse pulmonary outcomes. The study also demonstrated that lung injury after AKI was regulated by inflammation and inflammatory crosstalk between the kidney and lung.

Clinical implications

Study findings offer a compelling rationale to introduce postnatal anti-inflammatory therapies in newborns, such as nitric oxide and caffeine. Known for their efficacy in adults and preclinical studies, these therapies warrant evaluation to potentially prevent AKI or repair the lung after AKI.

The neonatal models also provide opportunities to study mechanisms of kidney-lung crosstalk and novel therapeutics in the context of acute kidney injury in a premature infant. This work extends previously published models of AKI in adults and adolescents, complements existing findings and underscores the importance of cross-institutional collaboration to address key research inquiries.