title: Aminoglycoside-induced nephrotoxicity in children.
abstract: Aminoglycoside antibiotics, in particular gentamicin and tobramycin, are still commonly used in paediatric clinical practice. These drugs cause nephrotoxicity, which particularly affects the proximal tubule epithelial cells due to selective endocytosis and accumulation of aminoglycosides via the multi-ligand receptor megalin. Recent epidemiological studies, using more widely accepted definitions of acute kidney injury (AKI), have suggested that AKI may occur in between 20 and 33 % of children exposed to aminoglycosides. A consensus set of phenotypic criteria for aminoglycoside-induced nephrotoxicity have recently been published. These are specifically designed to provide robust phenotyping for pharmacogenomic studies, but they can pave the way for standardisation for all clinical studies. Novel renal biomarkers, in particular kidney injury molecule-1, identify aminoglycoside-induced proximal tubular injury earlier than traditional markers and have shown promise in observational studies. Further studies need to demonstrate a clear association with clinically relevant outcomes to inform translation into clinical practice. Extended interval dosing of aminoglycosides results in a reduction in nephrotoxicity, but its use needs to become more widespread. Inhibition of megalin-mediated endocytosis by statins represents a novel approach to the prevention of aminoglycoside-induced nephrotoxicity which is currently being evaluated in a clinical trial. Recommendations for future directions are provided.
authors.affiliation: Department of Women's and Children's Health, University of Liverpool, Liverpool, UK. stevemcw@liv.ac.uk.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: McWilliam
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Antoine
authors.affiliation: Institute of Child Health, University College London, London, UK.
authors.forename: Rosalind L
authors.initials: RL
authors.lastname: Smyth
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors.forename: Munir
authors.initials: M
authors.lastname: Pirmohamed
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000175:diagnosis / Q000628:therapy; D000293:Adolescent; D000617:Aminoglycosides / Q000008:administration & dosage / Q000009:adverse effects*; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000009:adverse effects*; D015415:Biomarkers; D002648:Child; D002675:Child, Preschool; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007668:Kidney / Q000187:drug effects / Q000473:pathology
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D015415:Biomarkers
keywords: Acute kidney injury; Aminoglycoside; Biomarker; Kidney injury molecule-1; Nephrotoxicity