Tamara van Donge

Dynamics of creatinine in ELBW neonates 141 7 aspects (e.g. as a result of GA or increasing PNA), or due to pathophysiological conditions (e.g. asphyxia or sepsis). For instance, an increase in Scr during the first days of life simply reflects that creatinine production is greater than the eliminated amount per day, up to day 2-3 after birth. The decline in Scr afterwards reflects ongoing postnatal maturation. Observing a substantial increase in Scr after birth for an ELBW neonate born at 32 weeks GA, could reflect a pathological condition (e.g. acute kidney injury) rather than immaturity of the kidney. 30 Along the same line, the absence of a Scr decrease may reflect impaired kidney function. Although this study is not focusing on acute kidney injury in ELBWneonates, it needs to be acknowledged that physiological events early after birth cause these parameters to change irrespective of acute kidney injury and that neonatal physiology must be considered in neonatal-specific definition of acute kidney injury. 31 In conclusion, we report the first mathematical model that is able to characterize creatinine dynamics in ELBW neonates during the first six weeks of life in a quantitative manner. Three investigated characteristics influence creatinine clearance, namely GA and MOD (influencing maturation of clearance) and treatment with ibuprofen (directly influencing clearance, but not impeding its maturation), while prenatal lung maturation or the need for treatment with inotropic agents were no significant covariates. Gestational age is further the major determinant for the initial creatinine concentration after birth (increasing 6% per week of GA) suggesting gestational-dependent maternal creatinine transfer to the maternal compartment until birth. The model-derived GA adjusted reference intervals for ELBW neonates provides a rationale for normative Scr concentrations and as suchmay assist clinicians to further optimize monitoring and treatment decisions in this vulnerable patient population, or to assess adverse drug reactions. This study illustrates a physiological approach to establish population specific reference ranges, as neonatal physiology is distinctive from that of older infants, and suggests a methodological approach to attain this. Declarations Funding Tamara van Donge, Verena Gotta, John van den Anker and Marc Pfister are funded by the Eckenstein-Geigy foundation. Elena Levtchenko is funded by F.W.O. Vlaanderen, grant 1801110N. The research activities of Anne Smits are supported by the Clinical Research and Education Council of the University Hospitals Leuven. Ethics approval This retrospective study was in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The local ethics committee of University Hospitals Leuven approved this study (internal study number S63405).