When will the glomerular filtration rate in preterm neonates catch up to their term peers?

Yunjiao Wu (1), Karel Allegaert (2,3), Robert B. Flint (2,4), Sebastiaan C Goulooze (5), Pyry A J Välitalo (6,7), Sinno H.P. Simons (4), Elke H.J. Krekels (1), Catherijne A.J. Knibbe (1,4,8,9), Swantje Völler (1,4,9)

1. Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands. 2. Department of Hospital Pharmacy, Erasmus University Medical Center, Rotterdam, The Netherlands 3. KU Leuven, Departments of Development and Regeneration and Pharmaceutical and Pharmacological Sciences, Leuven, Belgium 4. Department of Pediatrics, Division of Neonatology, Erasmus MC Sophia Children's Hospital, Rotterdam, The Netherlands 5. Leiden Experts on Advanced Pharmacokinetics and Pharmacodynamics (LAP&P), Leiden, The Netherlands. 6. School of Pharmacy, University of Eastern Finland, Yliopistonranta 1 C, 70210 Kuopio, Finland 7. Finnish Medicines Agency, Microkatu 1, 70210 Kuopio, Finland 8. Department of Clinical Pharmacy, St Antonius Hospital, Nieuwegein, The Netherlands. 9. Division of Pharmacy, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands

Introduction

Glomerular filtration rate (GFR) plays an important role in the clearance of drugs in neonates. Characterizing its maturation provides a better understanding of renal function development and is helpful for the first dose selection of renally cleared drugs in neonates. Preterm birth has been associated with interrupted nephrogenesis while other factors during the neonatal period such as nephrotoxic drugs, hypotension, sepsis could further impact (the development of) their renal function. An important question is whether and at what age GFR in preterm neonates catch up to their term peers. Results from published studies are inconsistent and lack continuous data for preterm-born children across the entire childhood age range[1-8].

This study aims to build a model to describe the GFR in preterm and term neonates from birth to 18 years of age by simultaneously analyzing serum creatinine (Scr) and inulin clearance (CL) data.

Methods

Inulin CL data, which is the gold standard for measuring GFR, was retrieved from a previous paper[9] that collected individual inulin CL data from literature. As the inulin CL dataset did not include data on preterm-born children over three months of postnatal age (PNA), Scr concentrations from preterm and full-term children at various PNA from published studies[5, 10] and from data of individuals included the DINO study (NL47409.078.14, MEC-2014–067, NCT02421068) were added to the dataset.

A model was developed to simultaneously model inulin CL and Scr concentrations. Serum creatinine concentrations were assumed to be in steady state and determined by synthesis rate and GFR (Eq.1), while GFR was represented by inulin CL(Eq.2).

In Equation 1, the synthesis rate (Syn), as a connection between Scr and GFR, was selected from the published Schwartz and adjusted Schwartz equations for children[11-13], based on the fit of both Scr and inulin CL in preterm and term-born infants before the age of three months, when both markers were available. The best synthesis rate was then used to facilitate the model of GFR in preterm neonates from Scr concentrations after three month of age when inulin CL is lacking and only Scr concentrations are available.

The analysis was performed in NONMEM V7.4.3 (ICON Development Solutions, Ellicott City, MD, USA). Processing and visualization of output from NONMEM were performed in R 4.1.1 (CRAN.R-project.org). Model selection were based on OFV and Goodness Of Fit (GOF) plots split by gestational age (GA) and PNA. The final model was used to generate GFR values (expressed in ml/min) from birth to 18 years old for neonates with different GA.

Results

The final dataset contained a total of 1904 Scr concentrations from 384 neonates with median GA 29 (IQR 26-38) weeks, PNA 3903 (IQR 2.6-4015.0) days, and bodyweight of 28 kg (IQR 1.31-37.2) kg, and a total of 431 inulin CL values from 383 neonates with GA 36 weeks (IQR 31-40), PNA 3 (IQR 1-14) days and bodyweight of 2.4 (IQR 1.35-3.5) kg.

Pierce adjusted Schwartz equation[11] best described the synthesis rate of creatinine and was subsequently used in the model. Across the entire population, the GFR maturation was best described by Eq.3.

in which birthweight (Bwb) best described the prenatal maturation of GFR. The postnatal GFR maturation was best described by PNA in a sigmoidal equation, in which PNA₅₀, the time to reach half of the maximum GFR maturation, was determined by GA. The maximum GFR (GFRmax) (estimated at 6.83) was scaled by current bodyweight (Wt). The split GOF plots showed that the model described the Scr levels and the inulin CL well across different PNA and GA.

The results of the final model show that below one year of age, the largest differences in GFR are noted between different GA groups, and the fastest catch-up of preterm neonates. For a 26 GA weeks-born child at 1 month,  half-year, 1 year and10 year, its GFR accounts for 17%, 60%, 81% and 95% of the GFR of a 40 GA week-term born child at the same age, respectively. For a 35 GA weeks-born child, those values are 64%, 90%, 96% and 98.9%, respectively.

Conclusion

The difference in GFR between preterm and term neonates diminishes with age. During the first year of life preterm neonates shows fast catch-up to their term peer and reach at least around 80% of the GFR of their term peers at 1 year of age.

1. Vanpée, M., et al., Renal function in very low birth weight infants: normal maturity reached during early childhood. J Pediatr, 1992. 121(5 Pt 1): p. 784-8.
2. Gheissari, A., et al., Postnatal kidney function in children born very low birth weight. Iran J Kidney Dis, 2012. 6(4): p. 256-61.
3. Holzer, S., et al., Renal function in prepubertal children born with very low birthweight. Nutrition, 2019. 62: p. 20-24.
4. Restrepo, J.M., et al., Renal volume of five-year-old preterm children are not different than full-term controls. J Pediatr (Rio J), 2022. 98(3): p. 282-288.
5. Starzec, K., et al., Longitudinal assessment of renal size and function in extremely low birth weight children at 7 and 11 years of age. Pediatr Nephrol, 2016. 31(11): p. 2119-26.
6. Keijzer-Veen, M.G., et al., Renal function and size at young adult age after intrauterine growth restriction and very premature birth. Am J Kidney Dis, 2007. 50(4): p. 542-51.
7. Rakow, A., et al., Renal volume and function in school-age children born preterm or small for gestational age. Pediatr Nephrol, 2008. 23(8): p. 1309-15.
8. Salem, F., et al., Does “Birth” as an Event Impact Maturation Trajectory of Renal Clearance via Glomerular Filtration? Reexamining Data in Preterm and Full-Term Neonates by Avoiding the Creatinine Bias. The Journal of Clinical Pharmacology, 2021. 61(2): p. 159-171.
9. Wu, Y., et al., Prediction of glomerular filtration rate maturation across preterm and term neonates and young infants using inulin as marker. Aaps j, 2022. 24(2): p. 38.
10. Raaijmakers, A., et al., Ibuprofen exposure in early neonatal life does not affect renal function in young adolescence. Arch Dis Child Fetal Neonatal Ed, 2018. 103(2): p. F107-f111.
11. Pierce, C.B., et al., Age- and sex-dependent clinical equations to estimate glomerular filtration rates in children and young adults with chronic kidney disease. Kidney Int, 2021. 99(4): p. 948-956.
12. Schwartz, G.J., L.P. Brion, and A. Spitzer, The use of plasma creatinine concentration for estimating glomerular filtration rate in infants, children, and adolescents. Pediatr Clin North Am, 1987. 34(3): p. 571-90.
13. Schwartz, G.J., et al., New equations to estimate GFR in children with CKD. J Am Soc Nephrol, 2009. 20(3): p. 629-37.

Reference: PAGE 31 (2023) Abstr 10665 [www.page-meeting.org/?abstract=10665]

Poster: Drug/Disease Modelling - Paediatrics