Urinary Biomarkers of Aminoglycoside-Induced Nephrotoxicity in Cystic Fibrosis: Kidney Injury Molecule-1 and Neutrophil Gelatinase-Associated Lipocalin

Stephen J Mcwilliam,Rosalind L Smyth,Munir Pirmohamed,Daniel J Antoine,Andrea L Jorgensen

doi:10.1038/s41598-018-23466-4

Abstract

Aminoglycosides are commonly used for the treatment of pulmonary exacerbations in patients with cystic fibrosis (CF). However, they are potentially nephrotoxic. This prospective observational cohort study aimed to investigate the potential validity of two urinary renal biomarkers, Kidney Injury Molecule-1 (KIM-1) and Neutrophil Gelatinase-associated Lipocalin (NGAL), in identifying aminoglycoside-induced nephrotoxicity in children with CF. Children and young adults up to 20 years of age with a confirmed diagnosis of CF were recruited from ten United Kingdom hospitals. Participants provided urine samples for measurement of KIM-1 and NGAL concentrations, at baseline, at regular outpatient appointments, and before, during and after exposure to clinically-indicated treatment with the aminoglycoside tobramycin. 37/158 patients recruited (23.4%) received at least one course of IV tobramycin during the study. The median peak fold-change during tobramycin exposure for KIM-1 was 2.28 (IQR 2.69) and 4.02 (IQR 7.29) for NGAL, in the absence of serum creatinine changes. Baseline KIM-1 was positively associated with cumulative courses of IV aminoglycosides (R2 = 0.11; β = 0.03; p < 0.0001). KIM-1, in particular, may be a useful, non-invasive, biomarker of acute and chronic proximal tubular injury associated with exposure to aminoglycosides in patients with CF, but its clinical utility needs to be further evaluated in prospective studies.

Highlights

Renal function is currently evaluated clinically using serum creatinine measurement
This study investigates the potential of two urinary biomarkers, Kidney Injury Molecule-1 (KIM-1) and Neutrophil Gelatinase-associated Lipocalin (NGAL), in the identification of aminoglycoside-induced nephrotoxicity in children and young adults with cystic fibrosis (CF)
We present data collected from a prospective study demonstrating that, in children and young adults with CF, acute changes are observed in both urinary KIM-1 and NGAL during exposure to IV tobramycin

Summary

Introduction

Renal function is currently evaluated clinically using serum creatinine measurement. creatinine elevation is only seen when significant kidney damage has occurred[7], which means that identification of AKI is frequently late, and the degree of damage may be underestimated[8]. Impairment from aminoglycosides, there is a need for the development of improved biomarkers that reflect the site of toxicity, but can identify damage at an earlier stage than currently possible. This would, in turn, allow for treatment adjustment and the avoidance of any further decline in renal function. This study investigates the potential of two urinary biomarkers, Kidney Injury Molecule-1 (KIM-1) and Neutrophil Gelatinase-associated Lipocalin (NGAL), in the identification of aminoglycoside-induced nephrotoxicity in children and young adults with CF. KIM-1 is the only proximal tubule specific biomarker to have been formally qualified by regulatory agencies for use in preclinical drug development[9], and outperforms other markers in animal models of aminoglycoside-induced nephrotoxicity[10]. Our aims were three-fold: (1) to determine whether urinary KIM-1 and NGAL would be elevated during exposure to tobramycin in children with CF; (2) to determine whether the estimated glomerular filtration rate (eGFR) decreases with cumulative aminoglycoside exposure; and (3) whether any association exists between baseline urinary biomarker concentration and previous exposure

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