Background Megalin-mediated endocytosis is the prin-cipal pathway for the accumulation of aminoglycosides in proximal tubule epithelial cells,1 resulting in kidney toxicity. Activation of this pathway depends on intermediates derived from mevalonate, the product of 3-hydroxy-3-meth-ylglutaryl-coenzyme A (HMG-CoA) reduction, catalysed by HMG-CoA reductase.2 We hypothesised that inhibition of HMG-CoA reductase by statins would reduce uptake of aminoglycosides in the proximal tubule, leading to a re-duction in toxicity. This has previously been demonstrated in vitro.3 We tested this in two in vivo models.
Methods Sprague Dawley rats, (n=4/group) received in-traperitoneal (IP) dosing with saline (control), gentamicin (200 mg/kg/day), rosuvastatin (40 mg/kg/day), or gentami-cin and rosuvastatin for 9 days. Nephrotoxicity was measured using urinary N-Acetyl-β-d-glucosaminidase (NAG) and kidney injury molecule-1 (kim-1) on urine samples collected within 24 hours after the final dose. Male Hartley guinea pigs (n=6/group) received IP dosing with saline (control), gentamicin (100 mg/kg/day), statin, or combined gentami-cin and statin (simvastatin or rosuvastatin, 0.4 to 40 mg/kg/day) for 9 days. Nephrotoxicity was measured using serum creatinine and blood urea nitrogen (BUN) on urine samples collected within 24 hours after the final dose.
Results In rats co-administered rosuvastatin and gentami-cin, urinary concentrations of NAG and kim-1 were signifi-cantly lower than for gentamicin alone (p<0.01). In guinea pigs, rosuvastatin reduced gentamicin-induced nephro-toxicity in a dose-dependent manner: doses of 0.4, 4 and 40mg/kg/day led to 46% (p<0.01), 81% (p<0.0001), and 83% (p<0.0001) reductions, respectively, in serum creati-nine compared to animals receiving gentamicin only. Simi-lar results were seen with BUN. The minimum effective dose to prevent toxicity was 0.97mg/kg/day. Using a dose scaling algorithm this equates to a dose of 10mg/day in children. Simvastatin did not protect the kidney from gentamicin-in-duced nephrotoxicity. The results from the in vitro and in vivo animal studies led to the design of a phase IIa multi-centre, randomised, controlled clinical trial (RCT) in children with cystic fibrosis receiving clinically indicated treatment with aminoglycosides, where co-treatment with rosuvasta-tin (10mg) will be compared with current standard of care.
Conclusion Rosuvastatin inhibits gentamicin-induced nephrotoxicity in both rat and guinea pig models; in the latter, at therapeutic doses used in humans. This led to an RCT in children which has just completed recruitment. This bench-to-bedside translational research showcases the exciting area of drug repurposing with potential for signifi-cant patient benefit.
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