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.

Pharmacokinetics and safety of tobramycin nebulization with the I‐neb and PARI‐LC Plus in children with cystic fibrosis: A randomized, crossover study

“…Interestingly, no significant differences in KIM‐1/creatinine ratios between study visits were found in our study, while a recent review suggests that KIM‐1 outperforms other biomarkers in preclinical and clinical studies of aminoglycoside‐induced nephrotoxicity . This can be explained by the relatively high lower limit of quantitation (LLOQ) of 0.6 μg/L of our KIM‐1 assay, while the median KIM‐1 reference value for healthy children is expected to be around 0.410 μg/L (interquartile range 0.226–0.703 μg/L) .…”

“…Interestingly, no significant differences in KIM-1/creatinine ratios between study visits were found in our study, while a recent review suggests that KIM-1 outperforms other biomarkers in preclinical and clinical studies of aminoglycoside-induced nephrotoxicity. 31 Those patients may be even more at risk for TIS-induced renal toxicity, since there is no recovery time in an off-period.…”

Electronic Health Record–Enabled Big‐Data Approaches to Nephrotoxin‐Associated Acute Kidney Injury Risk Prediction

“…Another advance has been in the area of AKI biomarkers. Although these biomarkers still technically detect injury after it occurs, their rise precedes that of serum creatinine concentration, leading to earlier identification of nephrotoxicity . Biomarkers have been studied most extensively in general AKI populations; however, NTx‐AKI is an especially promising area for biomarker research .…”

Repurposing Statins for Renal Protection: Is It a Class Effect?

“…Aminoglycoside‐induced nephrotoxicity is characterized by selective targeting of the proximal tubule epithelial cells within the renal cortex. Intracellular aminoglycoside results in apoptosis and necrosis of these cells via a variety of pathways (including mitochondrial dysfunction and the release of reactive oxygen species) ( Figure ) . Aminoglycosides accumulate in proximal tubule cells through endocytosis via the multi‐ligand receptor, megalin.…”

“…Intracellular aminoglycoside results in apoptosis and necrosis of these cells via a variety of pathways (including mitochondrial dysfunction and the release of reactive oxygen species) (Figure 1). 5 Aminoglycosides accumulate in proximal tubule cells through endocytosis via the multi-ligand receptor, megalin. Consistent with this, in megalin knockout mice, there is no renal accumulation of aminoglycosides.…”