Tamara van Donge

Dynamics of creatinine in ELBW neonates 137 7 also, albeit to a lesser extent, reflected by the maternal creatinine concentrations which are generally, but marginally lower during the second trimester (0.59 mg/dl) as compared during the third trimester (0.61 mg/dl). 21 Third, we illustrated a clear relationship between creatinine clearance and Scr concentrations, starting after the first postnatal days (Figure 2). Adaptation to extra-uterine life or maternal Scr contribution might be potential hypotheses for lack of relationship between creatinine clearance and Scr concentrations on the first day after birth, although this requires further investigation. Overall, it demonstrates that Scr concentrations, which are routinely collected directly after and during the first days after birth, can be interpreted and can provide crucial understanding on the developing kidney function. In addition, we recognize the unit policy was to obtain Scr concentrations frequently. This can be illustrated by comparing our median number of observations (n=20/patient) to a recent reference study, like the Assessment of Worldwide Acute Kidney Epidemiology in Neonates (AWAKEN) study, where the median number of Scr concentrations was ≤3 and ≤5 per patient, respectively in 10 and 15 of the contributing units. 22 Fourth, in this study antibiotic treatment (e.g. aminoglycosides) has not been assessed as a covariate on any of the model parameters. Since most ELBW neonates in the NICU of the study patients receive this type of empiric treatment in early neonatal life, we considered this as a non-distinctive feature of our population. The same holds true for nutritional and fluid management strategies. As these interventions are standardized, we were unable to explore these factors. Continuing with drug effects, this study confirms that ibuprofen treatment is associated with a transient decrease in creatinine clearance, although this effect is relatively small (Figure 4). In contrast, the prescription of inotropic agents was not associated with changes in Scr or creatinine clearance in these datasets. It has to be acknowledged that the dose or exact ibuprofen administration time point during the day is not taken into account; ibuprofen treatment was only assessed as a binary factor on the creatinine clearance for each postnatal day. As such our analysis may underestimate the effect of ibuprofen treatment on kidney function. Utilized ibuprofen dosing regimen was according to label (10 mg/kg, followed by 5 mg/kg/day every 24 hours, for two to four additional days) and was not adapted for the proven increase in ibuprofen clearance with increasing postnatal age. 23 However, we confirm that the model as constructed is indeed fitted to explore potential difference in the incidence and severity of renal impairment and/or acute kidney injury (AKI) between different dosing strategies.