title: Mechanism-based urinary biomarkers to identify the potential for aminoglycoside-induced nephrotoxicity in premature neonates: a proof-of-concept study.
abstract: Premature infants are frequently exposed to aminoglycoside antibiotics. Novel urinary biomarkers may provide a non-invasive means for the early identification of aminoglycoside-related proximal tubule renal toxicity, to enable adjustment of treatment and identification of infants at risk of long-term renal impairment. In this proof-of-concept study, urine samples were collected from 41 premature neonates (≤ 32 weeks gestation) at least once per week, and daily during courses of gentamicin, and for 3 days afterwards. Significant increases were observed in the three urinary biomarkers measured (Kidney Injury Molecule-1 (KIM-1), Neutrophil Gelatinase-associated Lipocalin (NGAL), and N-acetyl-β-D-glucosaminidase (NAG)) during treatment with multiple courses of gentamicin. When adjusted for potential confounders, the treatment effect of gentamicin remained significant only for KIM-1 (mean difference from not treated, 1.35 ng/mg urinary creatinine; 95% CI 0.05-2.65). Our study shows that (a) it is possible to collect serial urine samples from premature neonates, and that (b) proximal tubule specific urinary biomarkers can act as indicators of aminoglycoside-associated nephrotoxicity in this age group. Further studies to investigate the clinical utility of novel urinary biomarkers in comparison to serum creatinine need to be undertaken.
authors.affiliation: MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: McWilliam
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Antoine
authors.forename: Venkata
authors.initials: V
authors.lastname: Sabbisetti
authors.forename: Mark A
authors.initials: MA
authors.lastname: Turner
authors.forename: Tracey
authors.initials: T
authors.lastname: Farragher
authors.forename: Joseph V
authors.initials: JV
authors.lastname: Bonventre
authors.forename: B Kevin
authors.initials: BK
authors.lastname: Park
authors.forename: Rosalind L
authors.initials: RL
authors.lastname: Smyth
authors.forename: Munir
authors.initials: M
authors.lastname: Pirmohamed
mesh_terms: D000118:Acetylglucosaminidase / Q000652:urine*; D058186:Acute Kidney Injury / Q000139:chemically induced / Q000175:diagnosis* / Q000652:urine; D000209:Acute-Phase Proteins / Q000652:urine*; D000617:Aminoglycosides / Q000009:adverse effects*; D000900:Anti-Bacterial Agents / Q000009:adverse effects*; D015415:Biomarkers / Q000652:urine; D005260:Female; D005839:Gentamicins / Q000009:adverse effects; D000072596:Hepatitis A Virus Cellular Receptor 1; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D000071068:Lipocalin-2; D054834:Lipocalins / Q000652:urine*; D008297:Male; D008562:Membrane Glycoproteins / Q000652:urine*; D011518:Proto-Oncogene Proteins / Q000652:urine*; D011991:Receptors, Virus
chemical_list: D000209:Acute-Phase Proteins; D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D015415:Biomarkers; D005839:Gentamicins; C491143:HAVCR1 protein, human; D000072596:Hepatitis A Virus Cellular Receptor 1; C489506:LCN2 protein, human; D000071068:Lipocalin-2; D054834:Lipocalins; D008562:Membrane Glycoproteins; D011518:Proto-Oncogene Proteins; D011991:Receptors, Virus; D000118:Acetylglucosaminidase