Establishing predictive indicators, or biomarkers, of aminoglycoside nephrotoxicity and the Incidence of ototoxicity in children up to six years with cystic fibrosis (PIANO-CF extension)
AuthorMunro, Courtney Bree
Document TypePhD thesis
Access StatusThis item is embargoed and will be available on 2021-10-29. This item is currently available to University of Melbourne staff and students only, login required.
© 2019 Courtney Bree Munro
Cystic Fibrosis (CF) is an autosomal recessive condition caused by a mutation in the cystic fibrosis transmembrane regulator (CFTR) gene. It is commonly known as a disease affecting the lungs. Advances in screening, diagnosis and treatment of CF have led to enormous improvements in outcomes and life expectancy. Since pulmonary outcomes are better for patients from centres with aggressive and early use of antibiotic therapies, patients now have an earlier and longer lifetime exposure to antibiotics. People with CF are often treated with prolonged courses of aminoglycosides (AGs), for which known adverse effects include nephro- and ototoxicity. The resulting increase in longevity and ageing of the CF population has led to a paradigm shift from a focus on the lungs to management of a complex multi-system disease. The CFTR gene is abundantly expressed in the kidney, which has been considered ‘spared in CF’. However, renal complications are emerging in childhood with adolescents developing renal impairment and presenting with kidney failure. Correspondingly, renal impairment in CF has been largely attributed to nephrotoxic antibiotic exposure and, in particular, to AGs. Most importantly, it is necessary to recall the time before these complications were observed to understand the risk factors and how the development of renal impairment and kidney failure can be arrested. Acute kidney injury (AKI) is common in people treated with an intravenous AGs yet assessing the prevalence of AKI is difficult and complicated by a multitude of definitions. Serum creatinine is considered the ‘gold standard’ for the detection of AG-induced nephrotoxicity in AKI classification systems, yet it is neither specific nor sensitive and has many limitations, particularly in CF. Predictive indicators and novel renal biomarkers may allow earlier detection of AG-induced nephrotoxicity and provide an opportunity to mitigate risk, the progression AKI and subsequent renal impairment and chronic kidney disease. The primary aim of this study was to investigate predictive indicators and novel renal biomarkers of AG-induced nephrotoxicity in young children with CF in the setting of acute AG exposure. We also sought to uncover whether expression of novel renal biomarkers differed between children with CF and healthy controls—and whether previous AG exposure played a role in this. The secondary aim of this study was to investigate hearing impairment and whether there was a correlation between hearing impairment and cumulative intravenous AG exposure. The predictive indicators that were studied include serum cystatin C, serum magnesium, fractional excretion of magnesium and urinary beta-2-microglobulin. The novel renal biomarkers that were studied include kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, interleukin-18, liver-type fatty acid binding protein and fibroblast growth factor-23. All novel renal biomarkers were measured in urine and for a small cohort, we additionally measured kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin in serum. We also studied hearing at three time points, investigating hearing impairment and ototoxicity in young children with CF in the setting of acute intravenous AG exposure, with longitudinal follow-up up to approximately one year. In children with CF and acute intravenous AG exposure, we observed AKI, no significant change in estimated glomerular filtration rate, hypomagnesaemia with increased fractional excretion of magnesium that resolved, no correlation between serum creatinine and serum cystatin C and significant changes in urinary kidney injury molecule-1 and urinary neutrophil gelatinase-associated lipocalin. A comparison of gentamicin and tobramycin showed significant differences with higher fractional excretion of magnesium, when corrected for difference in dose, and higher levels of kidney injury molecule-1 in children who received gentamicin. Children with CF showed hyperfiltration and increased fractional excretion of magnesium at baseline. There was a large difference in the novel renal biomarkers (urinary kidney injury molecule-1, urinary neutrophil gelatinase-associated lipocalin and urinary fibroblast growth factor-23) between children with CF and healthy controls, irrespective of previous intravenous AG exposure. Hearing impairment was observed on 12% of tests; 7% of which was considered ototoxicity. We did not observe a correlation between hearing impairment and cumulative intravenous AG exposure. This is the first study of predictive indicators, novel renal biomarkers and long-term hearing follow-up in young children with CF. Our findings challenge the traditional view that the kidney is ‘spared’ in CF and suggest that the kidney in CF is different from the normal kidney, which may represent CF-related kidney disease. The results of this study suggest that novel renal biomarkers may be useful for detection of AG-induced nephrotoxicity in CF; however, they must first be understood in this population, as they differ significantly from healthy controls. Additionally, these findings provide insight into the rate of hearing impairment in young children with CF and challenge the traditional view that cumulative intravenous AG exposure increases the rate of hearing impairment. Further considerable work is required to better elucidate the comorbidities of kidney disease and hearing impairment faced by patients with CF. This study has informed on previously under-recognised phenomena and shown that the kidney is involved in CF. Further research in this field should better explicate the role of CFTR in the kidney, the extent of hyperfiltration and the expression of novel renal biomarkers in older children and adults with CF. With regard to hearing outcomes, future studies should consider how to screen for hearing impairment and how to ameliorate auditory ototoxicity using otoprotective agents.
Keywordscystic fibrosis; paediatrics; acute kidney injury; novel renal biomarkers; aminoglycosides; nephrotoxicity; ototoxicity
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