Acute kidney, liver injury risks with remdesivir pinned to underlying SARS-CoV-2 infection

Treatment with remdesivir in patients hospitalized for COVID-19 does not appear to confer increased risks of acute kidney (AKI) and liver injury (ALI), with a recent study showing that these risks are already elevated even before exposure to treatment and there is no further increase following remdesivir initiation.

In a cohort of 860 COVID-19 patients administered remdesivir during hospitalization in Hong Kong, 334 (38.8 percent) developed ALI and 137 (15.9 percent) AKI. The risks of both outcomes were already up to sevenfold high in the 2 days before remdesivir initiation (pre-exposure period) relative to baseline (from hospital admission to 3 days before treatment). The corresponding incidence rate ratios (IRRs) were 6.169 (95 percent confidence interval [CI], 4.549–8.365) for ALI and 7.074 (95 percent CI, 3.763–13.298) for AKI. [Aliment Pharmacol Ther 2022;doi:10.1111/apt.16894]

Of note, the risks of both ALI and AKI remained elevated with no further meaningful increase during remdesivir treatment. Compared to the pre-exposure period, the risk increases were not significantly higher in the first 2 days of treatment (ALI: IRR, 1.261, 95 percent CI, 0.915–1.737; AKI: IRR, 1.261, 95 percent CI, 0.889–1.789) and between days 2 and 5 of treatment (ALI: IRR, 1.087, 95 percent CI, 0.793–1.489; AKI: IRR, 1.152, 95 percent CI, 0.821–1.616).

ALI and AKI were defined based on serum abnormalities at any point during the observation period.

“The result does not suggest a significant association of remdesivir initiation with the risk of AKI and ALI. The increased risks of [both outcomes] after intravenous remdesivir treatment for COVID-19 may be due to the underlying SARS-CoV-2 infection,” according to the investigators.

With regard to AKI, the current findings are consistent with those of previous studies showing that remdesivir initiation does not lead to an increased risk. Furthermore, the drug is generally tolerated in patients with impaired renal function and kidney transplant patients. [BMC Nephrol 2021;22:52; Br J Clin Pharmacol 2021;87:4450-4454; Antimicrob Agents Chemother 2021;65:e02290–20; J Am Soc Nephrol 2020;31:1384-1386; Kidney Int Rep 2021;6:2305-2315]

“However, analysis of the WHO Safety database with other pharmaceutical treatments highlighted a 20-fold increased risk of acute renal failure, suggesting a disproportionality signal of remdesivir nephrotoxicity. This elevated risk could be caused by the concurring SARS-CoV-2 infection,” the investigators noted. [Clin Pharmacol Ther 2021;109:1021-1024]

In terms of ALI, the data are mixed regarding the risk of hepatotoxicity after remdesivir initiation, but mild transient elevations in liver enzymes were still described. [Am J Int Med 2020;8:285-288; Gastroenterol Hepatol 2020;18:2835; Am College Gastroenterol 2020;115:S523; Pharmacotherapy 2020;40:659-671]

“SARS-CoV-2 infection per se could lead to raised AST and ALT levels, through a variety of mechanisms including cytokine storm, hypoxic injury, and vascular thrombosis. Therefore, the elevation of liver enzymes during the course of COVID-19 was not solely attributable to the administration of remdesivir,” explained the investigators. [J Pathol 2004;203:631-637; Nat Rev Gastroenterol Hepatol 2021;18:348-364; J Hepatol 2020;73:807-816]

In Hong Kong, remdesivir is one of the treatment options for patients hospitalized with COVID-19, especially those with severe but noncritical disease (oxygen saturation <94 percent on room air). The recommended dosage is 200 mg once for the first day and 100 mg once daily for the next 4 days or until hospital discharge. [https://www.ifem.cc/wp-content/uploads/2020/03/Communication-kit-Pneumonia_Wuhan.pptx; Gut 2021;70:733-742]

“The challenge of assessing the safety of remdesivir lay in its similar laboratory measures with COVID-19. Therefore, impaired kidney and liver functions should not be solely evaluated as a contraindication to remdesivir use,” according to the investigators. [Br J Clin Pharmacol 2021;87:4450-4454]

“However, should the clinical condition worsen or an acute liver or kidney injury develop after remdesivir initiation, discontinuation of remdesivir may be necessary and other treatment options should be explored,” they said.