Patent ductus arteriosus is associated with acute kidney injury in the preterm infant.

BACKGROUND: This study aimed to test the hypothesis that a patent ductus arteriosus (PDA) is independently associated with acute kidney injury (AKI) in neonates ≤ 28 weeks gestation. METHODS: Preterm infants with echocardiographic diagnosis of moderate-large PDA at age ≤ 30 days were studied retrospectively. AKI, the primary outcome, was defined and staged according to serum creatinine using Kidney Disease Improving Global Outcomes (KDIGO) neonatal criteria. Its association with the timing and duration of PDA, non-steroidal anti-inflammatory drugs (NSAIDs) and other nephrotoxic exposures, gestational age, and other covariates was evaluated using mixed-effects logistic regression models. RESULTS: Acute Kidney Injury occurred in 49% (101/206) of infants. Moderate-to-large PDA was associated with any-stage AKI (OR 5.31, 95% CI 3.75 to 7.53), stage 1 (mild) AKI (OR 4.86, 95% CI 3.12 to 7.56), and stages 2-3 (severe) AKI (OR 10.9, 95% CI 5.70 to 20.8). NSAID treatment added additional risk for mild AKI (OR 2.45, 95% CI 1.61 to 3.71). Severe AKI was less likely when NSAID treatment was effective (OR 0.45, 95% CI 0.21 to 0.97) but not when ineffective (OR 1.63, 95% CI 0.76 to 3.50). CONCLUSIONS: Moderate-to-large PDA was strongly associated with all stages of AKI in preterm infants ≤ 28 weeks of gestational age. Effective NSAID treatment decreased the risk of severe but not mild AKI. These differential effects reflect the balance between the renal benefits of PDA closure and the risk of NSAID toxicity.

Molecular mechanisms regulating the vascular prostacyclin pathways and their adaptation during pregnancy and in the newborn.

Prostacyclin (PGI(2)) is a member of the prostanoid group of eicosanoids that regulate homeostasis, hemostasis, smooth muscle function and inflammation. Prostanoids are derived from arachidonic acid by the sequential actions of phospholipase A(2), cyclooxygenase (COX), and specific prostaglandin (PG) synthases. There are two major COX enzymes, COX1 and COX2, that differ in structure, tissue distribution, subcellular localization, and function. COX1 is largely constitutively expressed, whereas COX2 is induced at sites of inflammation and vascular injury. PGI(2) is produced by endothelial cells and influences many cardiovascular processes. PGI(2) acts mainly on the prostacyclin (IP) receptor, but because of receptor homology, PGI(2) analogs such as iloprost may act on other prostanoid receptors with variable affinities. PGI(2)/IP interaction stimulates G protein-coupled increase in cAMP and protein kinase A, resulting in decreased [Ca(2+)](i), and could also cause inhibition of Rho kinase, leading to vascular smooth muscle relaxation. In addition, PGI(2) intracrine signaling may target nuclear peroxisome proliferator-activated receptors and regulate gene transcription. PGI(2) counteracts the vasoconstrictor and platelet aggregation effects of thromboxane A(2) (TXA(2)), and both prostanoids create an important balance in cardiovascular homeostasis. The PGI(2)/TXA(2) balance is particularly critical in the regulation of maternal and fetal vascular function during pregnancy and in the newborn. A decrease in PGI(2)/TXA(2) ratio in the maternal, fetal, and neonatal circulation may contribute to preeclampsia, intrauterine growth restriction, and persistent pulmonary hypertension of the newborn (PPHN), respectively. On the other hand, increased PGI(2) activity may contribute to patent ductus arteriosus (PDA) and intraventricular hemorrhage in premature newborns. These observations have raised interest in the use of COX inhibitors and PGI(2) analogs in the management of pregnancy-associated and neonatal vascular disorders. The use of aspirin to decrease TXA(2) synthesis has shown little benefit in preeclampsia, whereas indomethacin and ibuprofen are used effectively to close PDA in the premature newborn. PGI(2) analogs have been used effectively in primary pulmonary hypertension in adults and have shown promise in PPHN. Careful examination of PGI(2) metabolism and the complex interplay with other prostanoids will help design specific modulators of the PGI(2)-dependent pathways for the management of pregnancy-related and neonatal vascular disorders.