Tamara van Donge (1), Karel Allegaert (2,3,4), Verena Gotta (1), Anne Smits (2,5), John van den Anker (1,6), Marc Pfister(1)
(1) Pediatric Pharmacology and Pharmacometrics, University Children's Hospital Basel (UKBB), University of Basel, Basel, Switzerland, (2) Department of Development and Regeneration, KU Leuven, Leuven, Belgium, (3) Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium, (4) Department of Clinical Pharmacy, Erasmus MC, Rotterdam, The Netherlands, (5) Neonatal Intensive Care Unit, University Hospitals Leuven, Leuven, Belgium, (6) Division of Clinical Pharmacology, Children's National Hospital, Washington, DC, USA
Introduction: Accurate assessment of kidney function in extremely low birth weight (≤1000 gr, ELBW) neonates remains challenging as normative range of serum creatinine is still not well understood in this neonatal population. Passive reabsorption across immature leaky tubules contributes to transient accumulation of creatinine during the first days of life [1]. Aims of this study were (i) to characterize dynamics of serum creatinine concentration and associated creatinine clearance during the first 6 weeks of life, (ii) to develop time dependent creatinine reference ranges to facilitate clinical decision making in ELBW neonates.
Methods: Serum creatinine concentrations (analyzed by enzymatic assay) were collected in ELBW neonates during routine care in the neonatal intensive care unit of the University Hospitals Leuven, Belgium [2]. Change of serum creatinine and associated inter-individual variability (IIV) over time was characterized with non-linear mixed effect modelling (software package Monolix). A semi-mechanistic turn-over model assuming a constant creatinine production and age-dependent net creatinine clearance (due to postulated decrease in reabsorption) was used as structural model. Distribution volume of creatinine was set to equal total body water (~0.7 L/kg). Key covariates such as gestational age (GA), mode of delivery (MOD), birthweight, current weight, length, sex, treatment of ibuprofen (IBU) or inotropes were investigated applying a stepwise forward selection and backward deletion approach. Parameters of interest were (i) initial creatinine concentration after birth (Creabirth), (ii) time to decrease in postulated reabsorption by 50% (t50) and (iii) baseline creatinine clearance (CLBL).
Results: Creatinine concentrations (n=2826) from 148 ELBW neonates with median (range) GA and weight of 27 weeks (24-32 weeks) and 820 g (370-1000 g), respectively, were included in analyses. Creatinine concentrations were collected up to 42 days after birth with a median of 19 observations per patient. Creabirth was estimated to be 0.596 mg/dL at 27 weeks of gestational age (25.6% IIV), increasing 5% per week of GA. The parameter t50 was estimated to be 22.6 days, decreasing 8% with GA and being lower in neonates delivered by C-section. Ibuprofen treatment was associated with a 6% decrease in CLBL (26.2% IIV). Creatinine clearance at day 7 and day 42 of life amounted 0.357 and 0.697 ml/min for a preterm infant born at 24 weeks. For an infant born at 33 weeks, the estimated creatinine clearance was 0.484 and 0.758 ml/min at day 7 and day 42, respectively.
Conclusions: Developed semi-mechanistic model characterizes creatinine dynamics in ELBW neonates for the first time over a period of six weeks after birth in a quantitative manner. Three investigated factors influence creatinine clearance, namely GA, MOD and treatment of ibuprofen. GA is the major determinant for creatinine clearance in the first weeks of life. In addition to GA, both MOD and ibuprofen treatment influence the concentration profile and corresponding clearance of creatinine in this population. This might be explained by age-dependent maternal creatinine transfer before/at birth, age-dependent reabsorption of creatinine and the cardiac output in extremely low birth weight neonates. Characterized reference intervals provide a rationale for normative creatinine concentrations and can facilitate clinical decision making in these vulnerable patients.
References:
[1] Guignard J-P et al., (1999), Why do newborn infants have a high plasma creatinine? Pediatrics; 103: e49-e.
[2] George I et al. (2011), Postnatal trends in creatinemia and its covariates in extremely low birth weight (ELBW) neonates; Pediatr Nephrol 26, 1843–1849.
Reference: PAGE () Abstr 9324 [www.page-meeting.org/?abstract=9324]
Poster: Drug/Disease Modelling - Paediatrics