The Impact of Functional and Structural Maturation of the Kidney on Susceptibility to Drug and Chemical Toxicity in Neonatal Rodents

Drug responses are often unpredictable in juvenile animal toxicity studies; hence, optimizing dosages is challenging. Renal functional differences based on age of development will often result in vastly different toxicologic responses. Developmental changes in renal function can alter plasma clearance of compounds with extensive renal elimination. Absorption, distribution, metabolism, and excretion of drugs vary depending on animal age and kidney maturation. Toxicity can result in malformations or renal degeneration. Although renal morphologic development in humans generally occurs in utero, maximal levels of tubular secretion, acid-base equilibrium, concentrating ability, or glomerular filtration rate (GFR) are reached postnatally in humans and animals and subject to drug effects. Maturation of renal metabolism and transporters occurs postnatally and plays a critical role in detoxification and excretion. Maturation times must be considered when designing juvenile toxicity studies and may require cohorts of animals of specific ages to achieve optimal dosing schemes and toxicokinetics. In recent years, critical end points and windows of susceptibility have been established comparatively between species to better model pharmacokinetics and understand pediatric nephrotoxicity. There are examples of agents where toxicity is enhanced in neonates, others where it is diminished, and others where rat nephrotoxicity is expressed as juvenile toxicity, but in humans as gestational toxicity.