Ontogeny and cross species comparison of pathways involved in drug absorption, distribution, metabolism and excretion in neonates (review) : KIDNEY

The kidneys play an important role in many processes, including urine formation, water conservation, acid-base equilibrium, and elimination of waste. The anatomic and functional development of the kidney has different maturation time points in humans versus animals, with critical differences between species in maturation before and after birth. Absorption, distribution, metabolism, and excretion (ADME) of drugs vary depending on age and maturation, which will lead to differences in toxicity and efficacy. When neonate/juvenile laboratory animal studies are designed, a thorough knowledge of the differences in kidney development between newborns/children and laboratory animals is essential. The human and laboratory animal data must be combined to obtain a more complete picture of the development in the kidneys around the neonatal period and the complexity of ADME in newborns and children. This review examines the ontogeny and cross-species differences in ADME processes in the developing kidney in preterm and term laboratory animals and children. It provides an overview of insights into ADME functionality in the kidney by identifying what is currently known and which gaps still exist. Currently important renal function properties such as glomerular filtration rate, renal blood flow, and ability to concentrate are generally well known, while detailed knowledge about transporter and metabolism maturation is growing but is still lacking. Preclinical data in those properties is limited to rodents and generally covers only the expression levels of transporter or enzyme-encoding genes. More knowledge on a functional level is needed to predict the kinetics and toxicity in neonate/juvenile toxicity and efficacy studies

The interplay between drugs and the kidney in premature neonates

The kidney plays a central role in the clearance of drugs. However, renal drug handling entails more than glomerular filtration and includes tubular excretion and reabsorption, and intracellular metabolization by cellular enzyme systems, such as the Cytochrome P450 isoenzymes. All these processes show maturation from birth onwards, which is one of the reasons why drug dosing in children is not simply similar to dosing in small adults. As kidney development normally finishes around the 36th week of gestation, being born prematurely will result in even more immature renal drug handling. Environmental effects, such as extra-uterine growth restriction, sepsis, asphyxia, or drug treatments like caffeine, aminoglycosides, or non-steroidal anti-inflammatory drugs, may further hamper drug handling in the kidney. Dosing in preterm neonates is therefore dependent on many factors that need to be taken into account. Drug treatment may significantly hamper postnatal kidney development in preterm neonates, just like renal immaturity has an impact on drug handling. The restricted kidney development results in a lower number of nephrons that may have several long-term sequelae, such as hypertension, albuminuria, and renal failure. This review focuses on the interplay between drugs and the kidney in premature neonates.status: publishe

Adult Renal Size is Not a Suitable Marker for Nephron Numbers: An Individual Patient Data Meta-Analysis

Background: Renal size is often used as a marker for nephron numbers as estimation of glomerular numbers is not yet possible in vivo. However, the validity of an association between the two is questionable. As a proper marker for nephron number in an individual is needed in clinical practice, this study was designed to assess the association between renal size and nephron numbers. Methods: An individual patient data meta-analysis was performed on data retrieved with a PubMed and Embase search. Only studies were included that described individual human data on kidney size and nephron numbers determined by stereology, the gold standard methodology to estimate nephron numbers. As renal size increases until the end of puberty, and nephron numbers decline after the age of 60 years, only data from individuals aged 18-60 years without renal disease were included. Results: Six papers were identified that provided data on renal weight and nephron numbers from 114 individuals. Backward linear regression identified kidney weight and race as the only 2 significant factors explaining nephron numbers (R square 0.085, p=0.007). Controlling for race, there was a significant correlation between nephron number and kidney weight (r=0.231, r square=0.053, p=0.01). Conclusion: These data indicate that only ∼5% of the variation in nephron numbers is explained by differences in renal size. Renal size in adulthood should not be used as a marker for nephron numbers in an individual

MRI Imaging of Liver Fibrosis with Vitamin A Functionalized Magnetolipossomes in Rats

Garcia Ribeiro R.S., Van Santvoort A., Kektar-Atre A., de Schaepdrijver L., Bueters R., Rangarajan J.R., van Heerden M., Himmelreich U., ''MRI imaging of liver fibrosis with vitamin A functionalized magnetolipossomes in rats'', 2nd Belgian molecular imaging congress - BMIC 2015, April 22, 2015, Brussels, Belgium.status: publishe

Effect of drugs on renal development

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