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.