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.

Drosophila SLC22 Orthologs Related to OATs, OCTs, and OCTNs Regulate Development and Responsiveness to Oxidative Stress

“…Due to the lack of information regarding SLC22 fruit fly orthologs, we attempted to characterize and classify them utilizing multiple sequence alignments and RNAi knockdowns. Because there are minimal developmental phenotypes (apart from Octn2) for single SLC22 knockouts in mice despite developmentally interesting and highly dynamic expression patterns, developmental phenotypes observed in Drosophila could help further our understanding of how SLC22 contributes to development in other organisms as well [19,[28][29][30][31]. Prior to our analysis, only three (BalaT, CarT and SLC22A) out of the 25 fruit fly SLC22 orthologs were functionally investigated beyond global tissue expression screens and homology studies [5,10,15,43,51,52].…”

“…Without carnitine supplementation, Octn2 KO mice develop dilated cardiomyopathy, fatty livers and steatosis of other organs, and expire in 3-4 weeks [24]. Although Oat KO's (including Slc22a12) and Oct KO's have abnormal levels of metabolites and signaling molecules, with only one clear developmental phenotype observed thus far in mice, determining the functional importance of these genes in Drosophila could provide insight for orthologous developmental roles in mice and humans given their interesting developmental expression patterns [19,[28][29][30][31]. As an initial developmental screen, we created ubiquitous RNAi knockdowns driven by a ubiquitous da-GAL4 driver of 14 of the putative SLC22 orthologs and observed their development.…”

Pharmacokinetics of Hydrochlorothiazide in Children: A Potential Surrogate for Renal Secretion Maturation

“…During covariate exploration, maturation functions for glomerular filtration rate, and renal plasma blood flow were evaluated to describe the change of CL with age. 40,43 Compared to the final model, a slightly worse model fit (OFV = 3.0) was obtained from the model with fixed values of maturation function parameters for glomerular filtration rate, 43 and a substantially worse model fit (OFV = 22.9) was obtained from the model with fixed values of maturation function parameters for renal plasma blood flow. Importantly, the rise of OFV did not reach the statistical significance threshold when maturation values were fixed at prior estimates of glomerular filtration rate maturation; therefore, we cannot definitely rule out that HCTZ maturation ultimately develops similarly to glomerular filtration rate.…”

“…One human study examining para‐aminohippurate excretion in the kidney, which displays 90% renal excretion and is believed to be primarily mediated by OAT1 and OAT3, concluded that the maturation of OAT transporters increased markedly in the postnatal period and reached half of adult values at 2 years of age 40 . In the pediatric model characterized in this report, maturation parameters in our equations suggested that HCTZ CL/F reached half of adult CL/F values by 39.3 weeks PMA, which is earlier than the para‐aminohippurate study previously suggested in the murine and human models.…”

“…The similarity in children to adult clearance strengthens the finding in this report that the maturation of renal HCTZ transporters is likely earlier than previously published reports. During covariate exploration, maturation functions for glomerular filtration rate, and renal plasma blood flow were evaluated to describe the change of CL with age 40,43 . Compared to the final model, a slightly worse model fit (∆OFV = 3.0) was obtained from the model with fixed values of maturation function parameters for glomerular filtration rate, 43 and a substantially worse model fit (∆OFV = 22.9) was obtained from the model with fixed values of maturation function parameters for renal plasma blood flow.…”