A Population Model of Time-Dependent Changes in Serum Creatinine in (Near)term Neonates with Hypoxic-Ischemic Encephalopathy During and After Therapeutic Hypothermia
Wojciech Krzyżański, Pia Wintermark, Pieter Annaert, Floris Groenendaal, Suzan Şahin, Mehmet Yekta Öncel, Didem Armangil, Esin Koç, Malcolm Battin, Alistair J. Gunn, Adam Frymoyer, Valerie Y. Chock, Elif Keleş, Djalila Mekahli, John van den Anker, Anne Smits, Karel Allegaert
Abstract
Abstract The objective was to apply a population model to describe the time course and variability of serum creatinine (sCr) in (near)term neonates with moderate to severe encephalopathy during and after therapeutic hypothermia (TH). The data consisted of sCr observations up to 10 days of postnatal age in neonates who underwent TH during the first 3 days after birth. Available covariates were birth weight (BWT), gestational age (GA), survival, and acute kidney injury (AKI). A previously published population model of sCr kinetics in neonates served as the base model. This model predicted not only sCr but also the glomerular filtration rate normalized by its value at birth (GFR/GFR 0 ). The model was used to compare the TH neonates with a reference full term non-asphyxiated population of neonates. The estimates of the model parameters had good precision and showed high between subject variability. AKI influenced most of the estimated parameters denoting a strong impact on sCr kinetics and GFR. BWT and GA were not significant covariates. TH transiently increased $$\mathrm{sCr}$$ <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mi>sCr</mml:mi> </mml:math> in TH neonates over the first days compared to the reference group. Asphyxia impacted not only GFR, but also the $$\mathrm{sCr}$$ <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mi>sCr</mml:mi> </mml:math> synthesis rate. We also observed that AKI neonates exhibit a delayed onset of postnatal GFR increase and have a higher $$\mathrm{sCr}$$ <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mi>sCr</mml:mi> </mml:math> synthesis rate compared to no-AKI patients. Our findings show that the use of $$\mathrm{sCr}$$ <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mi>sCr</mml:mi> </mml:math> as marker of renal function in asphyxiated neonates treated with TH to guide dose selection for renally cleared drugs is challenging, while we captured the postnatal sCr patterns in this specific population. Graphical Abstract