An Aciclovir Intermediate Can Prevent Drug-induced Acute Kidney Injury

Supersaturation occurs readily in the kidney due to water reabsorption and can drive the precipitation of crystals within the nephron, resulting in acute kidney injury. With a focus on aciclovir – a common cause of acute kidney injury – we describe a design strategy which helped us identify a wide panel of potential inhibitors. We narrow this screen to 3 lead candidates which were tested at clinically relevant supersaturations in a simulated nephron. We find that our inhibitors inhibit both crystal nucleation and growth by kinetic mechanisms and that these inhibitors can be combined with synergistic effects. This enables us to force maintenance of supersaturation for the duration of the nephron retention time (the time it takes for renal filtrate to pass from the glomerulus through to the collecting duct) facilitating clinically desirable doses and derisking treatment associated adverse effects. We expect that our approach is not limited to this specific case and may be applied to a wide range of clinical contexts where transient, high supersaturations cause pathological crystal growth.