Novel approaches to aminoglycoside-induced nephrotoxicity in children

McWilliam, Stephen ORCID: 0000-0002-0509-7425 (2015) Novel approaches to aminoglycoside-induced nephrotoxicity in children. PhD thesis, University of Liverpool.

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Abstract

Background: Aminoglycoside antibiotics are commonly used in paediatric clinical practice, especially for the treatment of neonatal sepsis and pulmonary exacerbations in cystic fibrosis (CF). However, megalin-mediated endocytosis of the aminoglycosides by renal proximal tubule epithelial cells leads to toxicity, and may result in acute kidney injury and chronic kidney disease. Current approaches to identify and prevent toxicity are limited. Several novel biomarkers have shown utility in preclinical studies for the identification of aminoglycoside-induced nephrotoxicity, but clinical data and an understanding of their clinical utility is lacking. The potential of statins to prevent aminoglycoside-induced nephrotoxicity by inhibition of megalin-mediated endocytosis has been previously demonstrated in vitro and in a rat model, but its potential in man is unclear. Aims: Firstly, to investigate the utility of novel urinary biomarkers for the early identification of aminoglycoside-induced nephrotoxicity in children. Secondly, to develop a novel intervention using statins to prevent aminoglycoside-induced nephrotoxicity in children with CF. Methods and Results: Urine samples were collected from 41 premature neonates at least once per week, and daily during courses of gentamicin. Three urinary biomarkers were measured using Luminex-based (Kidney Injury Molecule-1 (KIM-1) and Neutrophil Gelatinase-associated Lipocalin (NGAL)) and colorimetric assays (N-acetyl-β-D-glucosaminidase (NAG)). All three biomarkers were elevated during treatment with gentamicin, but when adjusted for potential confounders, only the elevation in KIM-1 remained significant (mean difference from not treated, 1.35ng/mg urinary creatinine; 95% CI 0.05-2.65). Electrochemiluminescent assays for both KIM-1 and NGAL were validated, and were compared to Luminex-based assays by analysing samples from healthy children in the UK (n=120) and the US (n=171). 95% reference intervals for both biomarkers were derived using quantile regression. Urine samples were collected from a cohort of children with cystic fibrosis (n=158) at outpatient clinic appointments and during exposure to tobramycin. Biomarkers were measured using the validated electrochemiluminescent assays. Elevations in both KIM-1 and NGAL (median peak fold-change was 2.28 (IQR 2.69) and 4.02 (IQR 7.29) respectively) were observed during exposure to tobramycin. In a multiple regression model, baseline KIM-1 was associated with the number of previous courses of IV aminoglycoside (p

Item Type:	Thesis (PhD)
Additional Information:	Date: 2015-08 (completed)
Subjects:	?? RJ ?? ?? RM ??
Divisions:	Faculty of Health and Life Sciences
Depositing User:	Symplectic Admin
Date Deposited:	25 Aug 2016 15:49
Last Modified:	17 Dec 2022 02:27
DOI:	10.17638/02049479
URI:	https://livrepository.liverpool.ac.uk/id/eprint/2049479