A brief review of kidney development, maturation, developmental abnormalities, and drug toxicity: juvenile animal relevancy

Abstract

Nonclinical juvenile animal tests perform a valuable role in determining adverse drug effects during periods of organogenesis and/or functional maturation. Developmental anatomic and functional maturation time points are important to consider between juveniles and adults when regarding different organ toxicities in response to drug administration. The kidney is an example of a major organ that has differences in these time points in comparing juveniles to adults and in contrasting humans to laboratory animal species. Toxicologic pathologists, involved in juvenile studies, need to be aware of these time points which are age-related exposure periods of sensitivity to drug toxicity. Age-related developmental anatomic and functional maturation are factors which can affect the way that a drug is absorbed, distributed, metabolized, and excreted (ADME). Changes to any component of ADME may alter drug toxicity resulting in kidney abnormalities, nephrotoxicity, or maturational disorders. Juvenile animal kidneys may either be less resistant or more resistant to known adult nephrotoxic drug effects. Furthermore, drug toxicity observed in juvenile animal kidneys may not always correspond to similar toxicities in humans. Juvenile animal nonclinical toxicology studies targeting the kidneys have to be carefully planned to attain the maximum knowledge from each study.

Embryonic and foetal expression patterns of the ciliopathy gene CEP164

“…Notably, during murine development, the kidney, retina and cerebellum continue to develop postnatally. This reflects the chosen murine postnatal timepoints in this study, corresponding to estimated human embryonic and foetal developmental timepoints (S2-S4 Tables) [40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57].…”

Ontogeny and Cross-species Comparison of Pathways Involved in Drug Absorption, Distribution, Metabolism, and Excretion in Neonates (Review): Kidney

“…An overview of renal development and the nephrogenesis of the different species can be found in Table 1. The three main phases of in utero renal development include pronephros, mesonephros, and metanephros, with the latter forming the functioning kidney in vertebrates (Seely, 2017). Kidney formation involves a well-regulated balance between proliferation, differentiation, apoptosis, and morphogenesis (Frazier, 2017).…”

“…Functional maturation is closely related to the morphogenesis of the kidney. In all species, functional development lags behind anatomic maturation (Seely, 2017). During gestation, the homeostasis is mainly preserved by the placenta, whereas the contribution of the kidney starts to emerge in the third trimester (Chevalier and Norwood, 2011).…”

“…Factors in the neonatal kidney that influence absorption, distribution, metabolism, and excretion (ADME) properties of drugs include renal blood flow (RBF), glomerular filtration rate (GFR), and the tubular mass and lack of tubule maturity, with its impact on tubular secretion and absorption, maintenance of acid-base equilibrium, and urineconcentrating mechanisms. These functions are all reduced in the juvenile animal (Seely, 2017). In addition, the ontogeny of metabolizing enzymes, transporters, and transcription factors in the kidney all play a major role.…”

Alpha‐Tocopherol during lactation and after weaning alters the programming effect of prenatal high salt intake on cardiac and renal functions of adult male offspring

“…This age corresponds to 18–20 years of age in humans, ie a 2‐year period after the end of juvenile age (young adult offspring or young adulthood throughout). This period is considered a critical window for studies of drug toxicity, especially in the kidneys . We also investigated altered responses in mean arterial pressure (MAP) and heart rate (HR) to Ang II as a possible cause of these functional changes.…”