Dynamics of Organic Anion Transporter-Mediated Tubular Secretion during Postnatal Human Kidney Development and Maturation

Abstract

Background and objectives: The neonatal and juvenile human kidney can be exposed to a variety of potentially toxic drugs (e.g., nonsteroidal anti-inflammatory drugs, antibiotics, antivirals, diuretics), many of which are substrates of the kidney organic anion transporters, OAT1 (SLC22A6, originally NKT) and OAT3 (SLC22A8). Despite the immense concern about the consequences of drug toxicity in this vulnerable population, the developmental regulation of OATs in the immature postnatal kidney is poorly understood.

Design, setting, participants, & measurements: Recognizing that today it is difficult to obtain rich data on neonatal kidney handling of OAT probes due to technical, logistic, and ethical considerations, multiple older physiologic studies that used the prototypical organic anion substrate para-aminohippurate (PAH) were reanalyzed in order to provide a quantitative description of OAT-mediated tubular secretion across the pediatric age continuum. Parametric and semiparametric models were evaluated for kidney function outcome variables of interest (maximum tubular secretory capacity of PAH [Tm_PAH], effective renal plasma flow [ERPF], and GFR).

Results: Data from 119 neonates, infants, and children ranging in age from 1 day to 11.8 years were used to fit Tm_PAH, ERPF, and GFR as functions of postnatal age. Tm_PAH is low in the immediate postnatal period and increases markedly after birth, reaching 50% of the adult value (80 mg/min) at 8.3 years of age. During the first 2 years of life, Tm_PAH is lower than that of GFR when viewed as the fraction of the adult value.

Conclusions: During postnatal human kidney development, proximal tubule secretory function-as measured using PAH, a surrogate for OAT-mediated secretion of organic anion drugs, metabolites, and toxins-is low initially but increases rapidly. Despite developmental differences between species, this overall pattern is roughly consistent with animal studies. The human data raise the possibility that the acquisition of tubular secretory function may not closely parallel glomerular filtration.

Keywords: Adolescent; Anions; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Antiviral Agents; Cephapirin; Drug-Related Side Effects and Adverse Reactions; Hippurates; Infant, Newborn; Kidney Tubules, Proximal; Organic Anion Transporters; Renal Plasma Flow, Effective; Vulnerable Populations; clinical nephrology; diuretics; drug transporter; glomerular filtration rate; kidney; kidney development; pediatric nephrology; tubular secretion.

Graphical abstract

Figure 1.

Effective renal plasma flow (ERPF) as predicted by postnatal age using a generalized linear regression model. (A) Scatter plot of observed ERPF values (open circles) versus postnatal age. A regression line predicted by the model (solid line) and a smoothing spline curve fit to observed data (dashed line) are displayed. (B) Proportion of asymptotic ERPF during the first 2 years of life shown as model-predicted (solid line) and observed (dashed line) values.

Figure 2.

Maximum tubular secretory capacity of para-aminohippurate (Tm_PAH) as predicted by postnatal age using a generalized linear regression model. (A) Scatter plot of observed Tm_PAH values (open circles) versus postnatal age. A regression line predicted by the model (solid line) and a smoothing spline curve fit to observed data (dashed line) are displayed. (B) Proportion of asymptotic Tm_PAH during the first 2 years of life shown as model-predicted (solid line) and observed (dashed line) values.

Figure 3.

GFR as predicted by postnatal age using a generalized linear regression model. (A) Scatter plot of observed GFR values (open circles) versus postnatal age. A regression line predicted by the model (solid line) and a smoothing spline curve fit to observed data (dashed line) are displayed. (B) Proportion of asymptotic GFR during the first 2 years of life shown as model-predicted (solid line) and observed (dashed line) values.

Figure 4.

(A) Fraction of adult values of kidney function parameters as predicted by generalized linear regression models during the first 2 years of life. Effective renal plasma flow (ERPF, red), maximum tubular secretory capacity of para-aminohippurate (Tm_PAH, green), and GFR (blue) were each predicted as a function of postnatal age using logarithmically transformed linear regression models (B) GFR/Tm_PAH in 52 neonates, infants, and older children ranging in age from 7 days to 11.8 years.