Tamara van Donge

Abstract Background: Characterizing the dynamics of serum creatinine concentrations (Scr) and associated creatinine clearance (CLcr), as measure of kidney function in extremely low birth weight (≤1000 g, ELBW) neonates remains challenging. Methods: We performed a retrospective study that included longitudinal Scr (enzymatic assay) data from 148 ELBW neonates up to six weeks after birth. Change of Scr and inter-individual variability were characterized with non-linear mixed effect modelling. Key covariates such as gestational age (GA), mode of delivery (MOD) and treatment with ibuprofen or inotropic agents were investigated. Results: A total of 2814 Scr concentrations were analyzed. GA was associated with Scr at birth (higher with advancing GA), GA and MOD showed an association with postnatal maturation of CLcr (faster clearance increase with advancing GA and after C-section). Small CLcr decrease (≤5%) was quantified during ibuprofen treatment. For a GA of 27 weeks mean Scr (estimated CLcr) at birth was 0.61 mg/dl (0.23 ml/min), increasing to 0.87 mg/dl (0.27 ml/min) at day three, and decreasing to 0.36 mg/dl (0.67 ml/min) at day 42 after birth. Conclusions : We report the first mathematical model that is able to characterize Scr and CLcr in ELBW neonates during the first six weeks of life in a quantitative manner as a function of GA, MOD and ibuprofen treatment. This model allows to derive GA adjusted reference ranges for ELBW neonates, and provides a rationale for normative Scr concentrations and as such will help clinicians to further optimize monitoring and treatment decisions in this vulnerable patient population. Key words : reference ranges, glomerular filtration rate, creatinine reabsorption, ELBW neonates, model-based simulations Abbreviations: body surface area (BSA), baseline creatinine clearance (CL BL ), creatinine concentration at birth (crea birth ), extremely low birth weight (ELBW), gestational age (GA), glomerular filtration rate (GFR), ibuprofen treatment (IBU), inter-individual variability (IIV), mean prediction error (MPE), mean squared error (MSE), mode of delivery (MOD), neonatal intensive care unit (NICU), postnatal age (PNA), relative MPE (RMPE), relative root mean square error (RMSE), relative standard error (RSE), serum creatinine (Scr), time to decrease reabsorption by 50% (t 50 ), volume of distribution (Vd).