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

Abstract

Glomerular filtration rate (GFR) is an important measure of renal function. Various models for its maturation have recently been compared; however, these have used markers, which are subject to different renal elimination processes. Inulin clearance data (a purer probe of GFR) collected from the literature were used to determine age-related changes in GFR aspects of renal drug excretion in pediatrics. An ontogeny model was derived using a best-fit model with various combinations of covariates such as postnatal age, gestational age at birth, and body weight. The model was applied to the prediction of systemic clearance of amikacin, gentamicin, vancomycin, and gadobutrol. During neonatal life, GFR increased as a function of both gestational age at birth and postnatal age, hence implying an impact of birth and a discrepancy in GFR for neonates with the same postmenstrual age depending on gestational age at birth (ie, neonates who were outside the womb longer had higher GFR, on average). The difference in GFR between pre-term and full-term neonates with the same postmenstrual age was negligible from beyond 1.25 years. Considering both postnatal age and gestational age at birth in GFR ontogeny models is important because postmenstrual age alone ignores the impact of birth. Most GFR models use covariates of body size in addition to age. Therefore, prediction from these models will also depend on the change in anthropometric characteristics with age. The latter may not be similar in various ethnic groups, and this makes the head-to-head comparison of models very challenging.

Keywords: birth; glomerular filtration rate; maturation; neonates.

Figure 1

Fraction of adult GFR at birth increases with gestational age. The model predicts neonatal GFR as a fraction of the adult value (values in mL/min, not normalized for body size), at birth in preterm and full‐term neonates based on the gestational age at birth and body weight ratio. (A) GFR ratio in neonates born with median body weight (50th centile) at different gestational ages. Gray area shows this model predictions for neonates born with body weight within the 2nd and 98th centiles. (B) Predicted versus observed GFR ratios. The solid line is the line of unity, and broken lines are 2‐fold intervals around the line of unity. The observed data and references are reported in Table S1 of the supplementary material.

Figure 2

Fraction of adult GFR value from birth across the whole age range (values in mL/min, not normalized for body size). (A) Fraction of GFR versus postnatal age after birth until 25 years. (B) Fraction of GFR versus PMA until 25 years. (C) First 4 weeks of postnatal age from (A). (D) First few postmenstrual age weeks for subjects younger than 45 postmenstrual weeks. Gray circles represent observed in vivo data as a fraction of GFR values at each age relative to the mean adult reference value (114.3 mL/min). The black solid line is the best‐fit models to the observed ratios. Observed data are from the clinical studies reported in Table S1. The values of 500 and 1000 PNA weeks correspond to 9.6 and 19.2 years, respectively. (A) and (B) are in agreement at higher ages, when postnatal and postmenstrual ages are almost the same. The observed data and associated references are reported in Table S1 of the supplementary material.

Figure 3

Simulated GFR development from birth using different gestational ages at birth (A). The lines and associated symbols present the pattern of GFR development from birth onward with postmenstrual age (weeks) for the given gestational age at birth. The circles indicate the GFR value at birth for the given gestational age. Please note the y axis is on a logarithmic scale. Effects of increasing postmenstrual age on the GFR (B) as a ratio of adult absolute value (mL/min) and not normalized for size in premature neonates of varying gestational ages at birth.

Figure 4

Predicted and observed CL values for gentamicin, amikacin, vancomycin, and gadobutrol. Solid line is line of unity, and dashed lines are 2‐fold intervals. Observed data for these drugs are presented in Table S3 to Table S6.

Figure 5

Comparison of BSA (m²) versus age in children from different countries: (A) birth‐2 years, (B) 2‐12 years, (C) 12‐16 years. BSA was calculated using Haycock et al (1978) for BW below 15 kg and Du Bois and Du Bois (1989) for BW over 15 kg.

Figure 6

Predicted average GFR (mL/min) values in Japanese (A–C) and Dutch (D–F) pediatric subjects using different GFR models from the literature.