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.

Keywords: abnormalities; development; juvenile animals; kidney; maturation; toxicity.

Fig. 1.

Schematic of kidney development representing the pronephros (A), mesonephros (B), and metanephros (C). Modified from Patten and Saxén (schematic courtesy of David Sabio).

Fig. 2.

Nephrogenesis – Reciprocol Induction. The four initial steps of mesenchymal-to-epithelial transformation (MET) dependent on the close interaction of metanephric mesenchyme (MM) and the urinary bud (UB).

Fig. 3.

Schematic representation of nephrogenesis illustrating the configurational changes as nephrons develop. Modified from Saxén, Cho and Dressler, Dressler, and McMahon (schematic courtesy of David Sabio).

Fig. 4.

Histological appearance of postnatal day 11 rat kidney. Most glomeruli, particularly in the outer cortex, are immature appearing. Tubules are not fully mature.