Species Differences in Renal Development and Associated Developmental Nephrotoxicity

Abstract

The developing kidney is sensitive to both morphological and functional disturbances during the gestational and postnatal phases of growth and differentiation. Exposure to drugs or chemicals during these critical windows of renal development can result in aplasia, dysplasia, polycystic kidney disease, hydronephrosis, or other features characteristic of nephrotoxicity, including tubule dilation, necrosis, or mineralization. Functional effects can occur without associated morphological abnormalities. Differences in the timing of nephrogenesis and morphologic renal development among species help to explain specific phenotypes of various gestational and postnatal teratogens and nephrotoxins. Functional maturation follows anatomical maturation, but important differences in maximally achieved glomerular filtration rate, concentrating ability and acid-base equilibrium between species makes comparison of these timings critical for accurate and consistent translation of laboratory animal toxicity data to the human clinical experience. Species and age dependent differences in the maturation of kidney transporters, renal xenobiotic metabolism and renal blood flow can have a profound effect on the toxicity profiles of agents and marked differences in the tolerability based on age. Advances in the understanding of the genetics of inherited renal diseases and the underlying cellular and molecular pathogenesis of renal developmental anomalies has helped provide mechanistic understanding of many teratogenic and perinatal nephrotoxic agents. Investigative studies have provided important translational and mechanistic information for assessing human pediatric nephrotoxic potential. Birth Defects Research 109:1243-1256, 2017. © 2017 Wiley Periodicals, Inc.

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

“…Nephrogenesis. In 2017, a comparison of nephrogenesis by species was presented in detail by Frazier (2017) and included review of earlier authors (Owen and Heywood, 1986;Witte et al, 1986;Zoetis and Hurtt, 2003;Solhaug et al, 2004;Cappon and Hurtt, 2010;McMahon, 2016). 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). Nephrogenesis, which involves the final phases of kidney development and tubule differentiation, occurs in very different contexts between species (McMahon, 2016).…”

“…Though nephrogenesis begins in the fetus and is completed in humans before birth, it continues postnatally in the rat and is not completed until postnatal day (PND) 11-15 (Zoetis and Hurtt, 2003). In mice, most nephrons are fully formed by the end of gestation based on histomorphology (Zoetis and Hurtt, 2003;Frazier, 2017). In contrast, evidence in mice indicating labeled progenitor cells do not disappear until a few days after birth suggests nephrogenesis is not complete in mice until PND 2-4 (Short et al, 2014;McMahon, 2016).…”

“…The anatomic and functional development of the kidney has different maturation time points in man compared with laboratory animals. In addition to the knowledge of kidney development in humans, several reviews have been published on the comparative ontogeny of the developing kidney in different laboratory animals, which describe critical species differences in renal development and functional maturation before and after birth (Owen and Heywood, 1986;Witte et al, 1986;Zoetis and Hurtt, 2003;Solhaug et al, 2004;McMahon, 2016;Frazier, 2017).…”

“…Better understanding of these factors is needed to improve prediction of the ADME characteristics of drugs and chemicals administered to neonates. There are numerous examples of drugs that behave quite differently in adults and neonates that can be explained by the lack of maturation of various transporters or metabolic enzymes such as propofol, pazopanib, or dabrafenib, among many others (Groseclose et al, 2015;Frazier, 2017;Michelet et al, 2018;Frazier et al, 2019).…”