A randomised controlled trial of rosuvastatin for the prevention of aminoglycoside-induced kidney toxicity in children with cystic fibrosis

Stephen J Mcwilliam,Ashley P Jones,Alan R Smyth,Munir Pirmohamed,William Greenhalf,Thomas Jaki,Rosalind L Smyth,Anna Rosala-Hallas,Victoria Shaw

doi:10.1038/s41598-020-58790-1

Abstract

The PROteKT study tested the hypothesis that rosuvastatin can inhibit aminoglycoside-induced nephrotoxicity in children with Cystic Fibrosis (CF). This open label, parallel group, randomised controlled trial recruited children and young people aged 6 to 18 years with CF at 13 paediatric CF treatment centres in the UK. Participants were randomised equally to either receive oral rosuvastatin (10 mg once daily) or no intervention (control) throughout clinically indicated treatment with intravenous tobramycin. The primary outcome was the difference between the groups in mean fold-change in urinary Kidney Injury Molecule-1 (KIM-1). Fifty (rosuvastatin n = 23, control n = 27) participants were recruited between May 2015 and January 2017. Primary outcome data was available for 88% (rosuvastatin n = 20, control n = 24). The estimated mean treatment difference in the geometric mean-fold change of normalised KIM-1 was 1.08 (95% CI 0.87–1.35, p = 0.48). In total there were 12 adverse reactions, all mild, reported by five participants randomised to rosuvastatin, and one serious adverse event in each group. Whilst no protective effect of rosuvastatin was seen, there was a lower than expected level of nephrotoxicity in the cohort. Therefore, we can neither confirm nor refute the hypothesis that rosuvastatin protects against aminoglycoside nephrotoxicity.

Highlights

In Cystic fibrosis (CF) the resistant pathogen Pseudomonas aeruginosa is commonly implicated in secondary bacterial lung infections and colonisation
A multi-ligand receptor, facilitates the endocytosis and accumulation of aminoglycosides in these cells[11]. This pathway is activated by intermediates derived from mevalonate, which is formed from 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) via the enzyme HMG-CoA reductase[12]
We describe the first clinical trial to evaluate the repurposing of a statin for the prevention of aminoglycoside-induced kidney toxicity

Summary

Introduction

In Cystic fibrosis (CF) the resistant pathogen Pseudomonas aeruginosa is commonly implicated in secondary bacterial lung infections and colonisation. Aminoglycoside antibiotics, usually combined with a beta-lactam, are frequently used to treat respiratory exacerbations in CF1, as they are effective against P. aeruginosa Whilst this approach generally leads to improved patient outcomes, aminoglycoside use is associated with an increased risk of nephrotoxicity. Rosuvastatin was chosen as it is hydrophilic, has minimal hepatic metabolism, and has some renal elimination of the parent drug[21] (and theoretically preferable in preventing megalin-mediated uptake rather than a hepatically metabolised statin). It is highly potent, and licensed for use in children.

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