Introduction
The first aminoglycoside, streptomycin, was introduced into clinical practice in 1944, and has since been followed by many drugs of this class [
1]. The most common of these in clinical practice are gentamicin and tobramycin. The aminoglycosides are particularly active against aerobic Gram-negative bacteria, including Enterobacteriaceae and
Pseudomonas. Clinically, aminoglycosides may be used to provide targeted therapy, such as for the treatment of pulmonary exacerbations in children with cystic fibrosis colonised with
Pseudomonas aeruginosa. They are also used for the empirical treatment of suspected systemic sepsis, where they are given in combination with other antibiotics (such as gylcopeptide or beta-lactam antibiotics) to provide broad spectrum coverage of Gram-positive and Gram-negative bacterial species.
Nephrotoxicity, one of the most important adverse effects linked to aminoglycoside exposure, is associated with a varying degree of renal tubular dysfunction that may in the most severely affected patients lead to non-oliguric acute kidney injury (AKI) [
1]. This review has three aims: first, to evaluate what is currently known about aminoglycoside nephrotoxicity in children; second, to describe recent advances in the field, including novel diagnostics and therapeutic approaches; third, to provide recommendations on future directions for research.
Mechanisms of aminoglycoside-induced nephrotoxicity
Aminoglycoside-induced nephrotoxicity is characterised by selective targeting of the proximal tubule epithelial cells within the renal cortex. Approximately 5 % of the administered dose accumulates within these cells after glomerular filtration [
2]. Endocytosis via the multi-ligand receptor megalin has been demonstrated to be the principal pathway for this accumulation: megalin knock-out mice do not exhibit renal accumulation of aminoglycosides [
3]. Megalin is a ligand for numerous low-molecular-weight proteins (including albumin, vitamin D-binding protein, retinol-binding protein, α1-microglobulin and β2-microglobulin) and is highly expressed by proximal tubule epithelial cells [
4,
5], explaining the cell- and tissue-specificity of this toxicity.
Once inside the cell, aminoglycosides accumulate within lysosomes [
6], the Golgi apparatus and endoplasmic reticulum (ER) [
7], binding to phospholipids and inhibiting phospholipase activity, which results in lysosomal phospholipidosis [
6,
8]. At some unknown threshold concentration of aminoglycoside, leakage occurs from the lysosomal structures into the cytoplasm [
9]. Cytoplasmic aminoglycoside then acts both directly and indirectly on the mitochondria, activating the intrinsic pathway of apoptosis via cytochrome
c [
10] which in turn leads to the disruption of electron transport and ATP production and the formation of reactive oxygen species [
8]. Lysosomal cathepsins, released into the cytoplasm, also activate the intrinsic apoptotic pathway [
11] and, in higher concentrations, may cause necrosis [
12]. In the ER, aminoglycosides inhibit protein synthesis and associated ER functions, resulting in ER stress and apoptosis via calpain and caspase 12 [
13].
The reasons for inter-individual variability in susceptibility to aminoglycoside-induced nephrotoxicity are not clear. In particular, it is not known whether there are genetic factors which increase susceptibility, as has been reported for aminoglycoside-related hearing loss [
14]. No genome-wide studies have been undertaken in this area.
It can be hypothesised from the literature that mutations resulting in megalin deficiency would be protective, as in megalin knock-out mice [
3]. Other proteins also play a role in the pathway of megalin-mediated endocytosis. For example, the CIC-5 protein, which is defective in Dent’s disease, is involved in megalin trafficking [
15]. In their study on renal accumulation of aminoglycoside in CIC-5 knockout mice compared to controls, Raggi et al. observed that there was an 85 % reduction in gentamicin accumulation in the knockout mice [
15]. The same group also demonstrated a 15 % decrease in gentamicin accumulation in mice with defective
CFTR, the gene affected in cystic fibrosis, and hypothesised that CFTR may play a role in the pathway of megalin-mediated endocytosis [
15]. These results suggest that a genetic variant which impairs the megalin-mediated uptake pathway would therefore also provide some protection against aminoglycoside-induced nephrotoxicity. However, no human studies have as yet investigated this proposal.
Defining aminoglycoside-induced nephrotoxicity
A key difficulty in establishing the epidemiology of drug-induced kidney injury, including that caused by aminoglycosides, has been the absence of consensus criteria for diagnosing kidney damage. There are a number of classification systems for classifying AKI in children, of which the best validated are the paediatric-modified RIFLE (pRIFLE) criteria [
16,
17] and the Acute Kidney Injury Network (AKIN) criteria [
18]. The pRIFLE criteria depend on using estimated creatinine clearance, while the AKIN criteria are based on measured serum creatinine (Table
1). pRIFLE criteria seem to be the more sensitive of the two classification systems, but the AKIN criteria have a stronger association with poor outcomes, suggesting that they may be more specific [
19,
20]. More recently, the Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guideline for AKI [
21] has attempted to develop consensus (Table
1).
Table 1
Paediatric acute kidney injury definitions
‘Risk’ (R) | Decrease by 25 % | <0.5 ml/kg/h for 8 h | Stage 1 | ≥0.3 mg/dl (26.5 μmol/L) rise OR Increase to 1.5–1.99× baseline | <0.5 ml/kg/h for >6 h | Stage 1 | 1.5–1.9× baseline OR ≥0.3 mg/dl (≥26.5 μmol/l) increase | <0.5 ml/kg/h for 6–12 h |
‘Injury’ (I) | Decrease by 50 % | <0.5 ml/kg/h for 16 h | Stage 2 | Rise to ≥2–2.99× baseline | <0.5 ml/kg/h for >12 h | Stage 2 | 2.0–2.9× baseline | <0.5 ml/kg/h for ≥12 h |
‘Failure’ (F) | Decrease by 75 % OR Creatinine clearance of <35 ml/min/1.73 m2
| <0.3 ml/kg/h for 24 h OR anuria for 12 h | Stage 3 | Rise to ≥3× baseline OR ≥4 mg/dl (353.6 μmol/L) rise with an acute rise of at least 0.5 mg/dl (44 μmol/L) | <0.3 ml/kg/h for 24 h OR Anuria for 12 h | Stage 3 | 3.0× baseline OR Increase in serum creatinine to ≥4.0 mg/dl (≥353.6 μmol/l) OR Initiation of renal replacement therapy OR In patients aged <18 years, decrease in estimated glomerular filtration rate to <35 ml/min per 1.73 m2
| <0.3 ml/kg/h for ≥24 h OR Anuria for ≥12 h |
A standardised set of phenotypic criteria for drug-induced kidney disease (DIKD) has also recently been published by Mehta et al. [
22]. This work was initiated by the International Serious Adverse Event Consortium, following on from previous work by this group in developing phenotypic criteria for other drug-induced adverse events [
23]. Although the initial purpose of these criteria is to provide clear phenotypes for genetic studies of DIKD, they may also provide a consistent framework for all research in DIKD. Four phenotypes of DIKD have been proposed:
In relation to aminoglycoside-induced nephrotoxicity, the authors have suggested that it should be characterised by the AKI phenotype. The criteria for this phenotype are summarised in Table
2. An issue which also needs to be considered in a child with AKI is causality, i.e. whether the AKI is due to the infection for which the aminoglycoside was prescribed, or due to the drug per se. As there are no specific diagnostic tests for aminoglycoside nephrotoxicity, standardised causality assessment tools should be used, of which many have been described [
24].
Table 2
Suggested phenotypic criteria for drug-induced acute kidney injury, including that caused by aminoglycosides
• Rise in serum creatinine that presents as or progresses to stage 2 (KDIGO) 2–2.9× reference serum creatinine or higher • If child has a baseline serum creatinine of <0.5 mg/dl (44 μmol/L), must double serum creatinine to get to at least 0.5 mg/dl (44 μmol/L) or above OR • Decline by at least 50 % from peak serum creatinine over 7 days in relationship to change in drug-dosing adjustment or discontinuation within 2 weeks | • Oliguric <0.5 ml/kg per hour for 12 h (KDIGO stage 2) • Non-oliguric >1 ml/kg per hour for 24 h (paediatrics) • Urinalysis findings: granular and muddy casts consistent with acute tubular necrosis, urinary eosinophils, proteinuria • Fractional excretion of sodium of >1 % • Negative ultrasound findings • Positive gallium scan for acute interstitial nephritis • Clinical symptoms for acute interstitial nephritis: fever, rash and joint pains |
Epidemiology of aminoglycoside-induced nephrotoxicity in children
Children
Until recently, little data have been available documenting the incidence of aminoglycoside-induced nephrotoxicity in children, in part due to the lack of an accepted definition for AKI. However, following the recent advent of more widely accepted definitions of AKI in children, a number of studies have begun to address this question.
A retrospective cohort study at a tertiary children’s hospital in the USA used the pRIFLE criteria and the AKIN Staging definition to define aminoglycoside-induced nephrotoxicity [
19]. Of the 557 children who received aminoglycoside treatment for ≥5 days over the year of the study, the AKI rate was 33 and 20 % using the pRIFLE and AKIN criteria, respectively. AKI was associated with longer hospital stay and higher total hospital costs. The authors reported that whilst pRIFLE was more sensitive for the identification of AKI, AKIN was more strongly associated with patient outcomes.
Another factor limiting the quality of epidemiological data available is inconsistency among monitoring practices. In a prospective study of all admissions involving aminoglycoside exposure for ≥3 days at a tertiary paediatric centre in the USA, daily measurement of serum creatinine was used to monitor for AKI. AKI, defined by the pRIFLE criteria, was identified in 25 % of unique patients exposed to aminoglycosides and during 31 % of admission episodes [
25].
Neonates
Gentamicin is the drug most commonly prescribed to neonates in the UK [
26]. An American study found that 57.5 % of all neonates discharged from the neonate intensive care unit had received treatment with gentamicin [
27]. The UK National Institute of Health and Care Excellence (NICE) guidelines recommend the use of gentamicin (in combination with a penicillin) for first line therapy in neonates with suspected early-onset sepsis [
28]. Despite its widespread use, there are a paucity of data quantifying gentamicin-induced nephrotoxicity in neonates [
29].
A retrospective study of nephrotoxin exposure in preterm neonates at one U.S. centre documented gentamicin exposure in 86.0 % of the 107 neonates [
30]. In this cohort, 26.2 % developed AKI. Whilst this study cannot demonstrate causation, it does highlight the potential adverse impact of exposure to nephrotoxins in this population. A recent narrative review included ten studies of gentamicin use in neonates, where nephrotoxicity was assessed using plasma creatinine [
31]. Interestingly, seven of these studies reported no nephrotoxicity, while the remaining three reported various rates, the maximum being 27 % [
32]. This wide variation in rates again highlights the previous lack of standardised criteria for diagnosing aminoglycoside nephrotoxicity.
Children with cystic fibrosis
Cystic fibrosis (CF) is an autosomal recessive life-limiting disease which affects around 9000 people in the UK alone [
33]. The disease is characterised by the accumulation of thick secretions in the airways of the lungs that lead to reduced activity of the mucociliary escalator and predispose to secondary bacterial infection and pulmonary colonisation, often by resistant organisms, in particular
Pseudomonas aeruginosa. Approximately 25 % of children with CF aged 12–15 years have chronic pulmonary infection with
P. aeruginosa; this infection rate rises to 40 % by 16–19 years of age [
33].
Aminoglycosides have good efficacy against P. aeruginosa and are commonly used intravenously to treat pulmonary exacerbations in CF in combination with a beta-lactam antibiotic, such as ceftazidime. Treatment courses usually last for 2 weeks, and patients may have multiple courses of treatment throughout their lifetime.
A UK national survey of AKI in patients with CF found 24 cases between 1997 and 2004 [
34]; of these 88 % of patients were receiving an aminoglycoside at the time of developing AKI, or within the previous week. Identification of AKI relied on physician report and did not use standardised criteria—rather the AKI was defined as ‘raised plasma creatinine for age with or without oliguria’ [
34]. A follow-on case–control study identified an 80-fold increase in the risk of AKI if CF patients received an aminoglycoside within the preceding week [
35]. AKI was associated with significant acute morbidity, with 54 % requiring dialysis [
34].
The impact of daily monitoring of serum creatinine during treatment with aminoglycosides in children with CF has been assessed in a retrospective study in a tertiary paediatric centre in the USA [
36]. AKI was defined as a rise in serum creatinine by ≥0.3 mg/dl (26.5 μmol/L) within 48 h, or a 1.5-fold increase in the baseline serum creatinine level. Daily monitoring not only led to more cases of AKI being identified (in 21 of 103 courses, 20 %), but also an earlier identification of AKI. The authors of this study suggested that daily monitoring also led to changes in management (including increased use of once-daily dosing of aminoglycosides and intravenous (IV) fluids, reduced use of concomitant nephrotoxins and shorter courses of aminoglycosides) in an attempt to prevent or ameliorate AKI, although a randomised trial would be required to assess whether there was any impact on patient outcomes. In a second study, which had a case–control design, the same group identified that of the 593 admissions in which children were treated with an aminoglycoside for an exacerbation of CF [
37], there were 82 cases of AKI (14 %) which they felt were aminoglycoside-induced.
Long-term outcomes of aminoglycoside-induced nephrotoxicity
Nephrotoxin-associated AKI may lead to chronic kidney disease (CKD) [
38]. In a retrospective cohort study, children who developed AKI (using pRIFLE criteria) associated with nephrotoxin exposure (≥3 days of aminoglycosides or ≥3 nephrotoxins simultaneously for 1 day) had a relative risk of 3.84 [95 % confidence interval (CI) 1.57–9.40,
P <0.05] for developing one or more signs of CKD [reduced estimated glomerular filtration rate (GFR), hyperfiltration, proteinuria, or hypertension] at 6 months compared to controls (nephrotoxin exposure, but no AKI) [
38].
The long-term effects of multiple exposures to aminoglycosides are less clear. In a cohort of adults with CF from Liverpool, chronic renal impairment (as measured by reduced creatinine clearance) was reported in 31–42 % of adult CF patients (depending on definition) and was associated with cumulative aminoglycoside exposure (
P= 0.0055) [
39]. This effect was exacerbated by the concomitant use of intravenous (IV) colistin, although IV colistin alone did not have an impact on renal function [
39]. A previous, slightly smaller study in a Danish CF centre using tobramycin found no association between previous tobramycin exposure and measured creatinine clearance [
40].
Future directions
It is only recently, with the advent of standardised definitions of AKI, that studies have begun to shed more light on the epidemiology of aminoglycoside-induced nephrotoxicity. Large observational cohort studies of both paediatric and adult patients being treated with aminoglycosides are needed. However, the design of such studies is important. First, these would need to use a standardised definition of AKI [such as the KDIGO guideline (Table
1)] alongside standardised phenotypic criteria for aminoglycoside-induced nephrotoxicity (Table
2) [
22]. Second, they should include baseline and serial measurements of novel renal biomarkers, in particular KIM-1, in order to assess the predictive value of these markers for AKI. Third, DNA should be collected for pharmacogenomic analyses. This approach will allow for the description of the size of the problem using accepted definitions, an assessment of the potential clinical utility of novel biomarkers and the identification of risk factors for the development of aminoglycoside-induced nephrotoxicity, including genetic factors.
The potential of novel, non-invasive, urinary biomarkers has been described. KIM-1 shows promise as a biomarker of acute and chronic proximal tubular injury associated with exposure to aminoglycosides [
47‐
50] and outperforms other biomarkers in pre-clinical studies [
46]. As described above, demonstrating a clear association with clinically relevant outcomes will inform future translation into clinical practice. Following this, further qualification of KIM-1, or any other promising biomarker, would be required through novel study designs (including RCT) where the measured biomarker concentrations are used to guide treatment decisions in patients exposed to aminoglycosides.
The development of improved diagnostic tools must be coupled with the development of further strategies to minimise the nephrotoxic consequences of aminoglycosides. A promising preventive strategy utilising statins has already been described and is currently being assessed in children with CF, using KIM-1 as the primary outcome measure. If successful, this intervention will require assessment in a large, phase III RCT using a standardised definition of AKI as the primary outcome measure in order to pave the way for widespread clinical application.
Conclusion
Clinicians considering the use of aminoglycosides for the treatment of infection in their patients will be well aware of the potential for nephrotoxicity to occur with these antibiotics. Despite changes to practice, such as extended interval dosing, nephrotoxicity still occurs. Novel renal biomarkers, in particular KIM-1, may lead to the earlier identification of nephrotoxicity, ultimately allowing for timely intervention to prevent further kidney injury. Preventive strategies may ultimately lead to further changes in clinical practice that significantly improve the benefit–risk ratio of aminoglycosides which is much needed in the current environment where the rise of antimicrobial resistance poses a major threat to the global population.
Acknowledgments
SJM is a NIHR Academic Clinical Lecturer. His PhD research was completed as a MRC Clinical Training Fellow supported by the North West England Medical Research Council Fellowship Scheme in Clinical Pharmacology and Therapeutics, which is funded by the Medical Research Council (grant number G1000417/94909), ICON, GlaxoSmithKline, AstraZeneca and the Medical Evaluation Unit. DJA would like to acknowledge financial support from a Royal Society International Travelling Research Fellowship and the Wellcome Trust. All authors would also like to thank the MRC Centre for Drug Safety Science for support. Both MP and RLS are NIHR Emeritus Senior Investigators.
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