The adverse renal effects of prostaglandin-synthesis inhibition in the fetus and the newborn

Abstract

OBJECTIVES:To summarize experimental animal data and to provide a limited literature review on the adverse renal effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on the developing fetus and the maturing newborn. DATA: The experimental data were obtained from anesthetized, ventilated, six-to eight-day-old rabbits that received an intravenous bolus of either acetylsalicylic acid (ASA), ibuprofen (IBU) or indomethacin (INDO). In one set of experiments, ASA was also tested in 12-week-old (young adult) rabbits. Renal function was monitored with inulin and para-aminohippuric acid clearances measuring glomerular filtration rate (GFR) and renal blood flow. The renal vascular resistance was calculated. All three nonspecific cyclo-oxygenase-1 or -2 (COX-1/2) inhibitors caused remarkably similar reversible, oliguric, acute renal failure (ARF). In young adult animals, the side effects were attenuated. The underlying pathophysiology is related to the carefully maintained low GFR of the fetus and the newborn, dependent on a delicate interplay between vasoconstriction (angiotensin II) and vasodilation (prostaglandins [PGs]). When PG-synthesis is inhibited, the vasoconstriction is relatively unopposed, causing ARF. LITERATURE REVIEW: The renal effects of fetal exposure to NSAIDs are discussed, as are new insights into the role of COX-1/2 for a normal nephrogenesis. COX-nil or COX-inhibited animals have long lasting renal structural injury. Fetuses exposed in utero to significant amounts of NSAIDs have at birth various degrees of renal insufficiency and structural renal defects with a very high mortality. CONCLUSIONS: All NSAIDs, both specific and nonspecific COX inhibitors, have renal side effects in the immediate postnatal period and should, therefore, be given with the utmost caution. NSAIDs given during pregnancy for the prevention of toxemia, polyhydramnios and premature labour may affect fetal renal function and structure. In animal experiments, IBU was not less nephrotoxic than INDO, as suggested recently by human premature neonates.

Development of an Automated Imaging Pipeline for the Analysis of the Zebrafish Larval Kidney

“…Additionally, pronephric tubular epithelium appeared flattened ( Figure S1I ). Thus, our data in larval zebrafish matches previously published data from other animal models confirming severe renal side effects of indomethacin on kidney development during nephrogenesis [ 50 ].…”

“…NSAIDs are widely used for closure of patent ductus arteriosus in preterms and are administered during pregnancy for prevention and treatment of toxemia, polyhydramnions and premature birth. However, exposure to NSAIDs during pregnancy can cause hypoperfusion of the fetal kidneys and acute renal failure in newborns with cystic changes of developing nephrons and long-term renal dysfunction [ 2 , 50 ]. In our study, concentrations of the non-selective COX1/COX2 inhibitor indomethacin had to be lowered due to 100% lethality at higher doses.…”

Síndrome de Bartter: una tubulopatía infrecuente de inicio antenatal

“…Se ha descrito el uso de indometacina en etapa prenatal para manejo del polihidroamnios antes de las semanas de embarazo, pero se debe considerar sus efectos en el cierre ductal con riesgo de hipertensión pulmonar postnatal que obliga a una monitorización estricta 20 .…”

Renal development in the fetus and premature infant

“…Fifty percent also received another nephrotoxin, indomethacin, as a non-surgical approach to close patent ductus arteriosus. Due to high renin–angiotensin levels in the preterm neonate, neonatal renal blood flow critically depends upon prostaglandin-induced vasodilation of afferent arterioles [141]. Thus, indomethacin can markedly reduce renal perfusion pressure and induce acute kidney injury (AKI) in a significant subset of neonates [140,142].…”