Jeremiah D Momper1, Jin Yang2, Mary Gockenbach2, Florin Vaida3, Sanjay K Nigam4. 1. Division of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, jmomper@ucsd.edu. 2. Division of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences. 3. Division of Biostatistics and Bioinformatics, Department of Family and Preventive Medicine, School of Medicine, and. 4. Department of Pediatrics and Medicine (Nephrology), School of Medicine, University of California, San Diego, La Jolla, California.
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 [TmPAH], 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 TmPAH, ERPF, and GFR as functions of postnatal age. TmPAH 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, TmPAH 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.
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 [TmPAH], 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 TmPAH, ERPF, and GFR as functions of postnatal age. TmPAH 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, TmPAH 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.
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