Tamara van Donge

Ibuprofen-related maturational adverse events in ELBW neonates 153 8 Introduction Extremely low birth weight infants (≤ 1000 g, ELBW) are born during active nephrogenesis, making their kidneys extremely vulnerable for damage by external factors such as exposure to nephrotoxic drugs or diseases such as neonatal sepsis. Although the development of nephrons will continue after preterm delivery, the final amount of nephrons will be less for infants who are born prematurely with an extremely low birth weight. 1-3 Serum creatinine is commonly used as surrogate biomarker for glomerular filtration rate as well as to assess kidney injury. Serum creatinine concentrations in preterm neonates are highly variable due to rapid changes in maturation (i.e. developmental physiology) and intercurrent events such as neonatal sepsis or therapeutic interventions for neonatal diseases. 4-7 The variations in serum creatinine values in these extreme preterm infants are still not fully understood and the accurate assessment of kidney function remains challenging. Although developed equations such as the (bedside) Schwartz formula support clinicians in estimating the glomerular filtration rate (GFR), the underlying physiology and the impact of pharmacotherapy has not been fully elucidated for ELBW neonates. 8,9 Recently, the quantitative effect of maturational changes such as gestational age and postnatal age, together with the impact of mode of delivery and ibuprofen treatment on the serum creatinine in ELBW neonates have been reported. 10 This study showed that gestational age was the major determinant for the initial creatinine concentration at birth, suggesting gestational-dependent maternal creatinine transfer until birth. 10 The fundamental aspects of neonatal clinical pharmacology such as exposure to a multitude of drugs, a highly variable population as reflected by the 10-fold difference in weight: 0.5 to 5 kg and rapid growth and development result in extensive within- and between-subject variability in drug disposition during the first months of life. 11,12 Ibuprofen, a nonsteroidal anti-inflammatory drug (NSAID) is often prescribed to preterm neonates as pharmacological treatment of a symptomatic patent ductus arteriosus and is known for its nephrotoxic side effects. 13 The nephrotoxic effects of ibuprofen are related to its mechanism of action (i.e. inhibition of cyclooxygenase resulting in decreased prostaglandin synthesis). 14 The induced prostaglandin inhibition of ibuprofen may result in renal hypoperfusion as prostaglandin E 2 , being synthesized along the nephron, contributes to the regulation of renal perfusion and GFR, by neutralizing the action of vasoconstrictive substances such as angiotensin II. 15,16 The ibuprofen effect further adds to the effects of renal hypoperfusion related to hemodynamic effects of a symptomatic patent ductus arteriosus. 15,16