Remdesivir nephrotoxicity in tubular epithelial cells

Introduction Remdesivir was the first antiviral drug approved to treat severe coronavirus disease 2019 (COVID-19). Nephrotoxicity was observed during preclinical development and longer duration of remdesivir therapy was associated with acute kidney injury (AKI) in patients with COVID-19, but its nephrotoxicity has been recently disputed. Methods Remdesivir cytotoxicity was assessed in murine and human proximal tubular cells cultured in 2-D and 3-D models, as well as in a mouse model of acute kidney injury. Results We now show that clinically relevant concentrations of remdesivir are cytotoxic to murine and human proximal tubular cells, either immortalized or in primary culture. Cytotoxicity was observed both in 2-D cultures and in spheroids and had morphological and functional features of necrosis. While mitochondrial dysfunction was observed, this appeared to be secondary to cytotoxicity and not a driver of cytotoxicity. Cell death could not be prevented by targeting proapoptotic caspases, nor by inhibiting necroptosis or ferroptosis programmed necrosis. Remdesivir metabolites were not cytotoxic. Interestingly, a short course of remdesivir that was not nephrotoxic by itself increased the severity of AKI induced by a cytokine storm elicited by bacterial lipopolysaccharide in mice. This is a clinically relevant context of use that may explain discrepancies related to the nephrotoxicity potential of short courses of remdesivir. Conclusion Remdesivir induces necrotic tubular cell death resistant to current interventions targeting programmed cell death, that becomes clinically relevant in the presence of permissive kidney hyperinflammation.