Remdesivir use and Risks of Acute Kidney Injury and Acute Liver Injury Among Patients Hospitalised With COVID-19

A Self-Controlled Case Series Study

Carlos K. H. Wong; Ivan C. H. Au; Wing Yiu Cheng; Kenneth K. C. Man; Kristy T. K. Lau; Lung Yi Mak; Sing Leung Lui; Matthew S. H. Chung; Xi Xiong; Eric H. Y. Lau; Benjamin J. Cowling

Disclosures

Aliment Pharmacol Ther. 2022;56(1):121-130. 

In This Article

Abstract and Introduction

Abstract

Background and Aim: To investigate and quantify the risks of AKI and ALI associated with remdesivir use, given the underlying diseases of SARS-CoV-2 infection.

Methods: This self-controlled case series (SCCS) study was conducted using electronic hospital records between 23 January 2020 and 31 January 2021 as retrieved from the Hong Kong Hospital Authority which manages all laboratory-confirmed COVID-19 cases in Hong Kong. Outcomes of AKI and ALI were defined using the KDIGO Guideline and Asia Pacific Association of Study of Liver consensus guidelines. Incidence rate ratios (IRR) for AKI and ALI following the administration of remdesivir (exposure) in comparison to a non-exposure period were estimated using the conditional Poisson regression models.

Results: Of 860 COVID-19 patients administered remdesivir during hospitalisation, 334 (38.8%) and 137 (15.9%) had incident ALI and AKI, respectively. Compared with the baseline period, both ALI and AKI risks were increased significantly during the pre-exposure period (ALI: IRR = 6.169, 95% CI = 4.549–8.365; AKI: IRR = 7.074, 95% CI = 3.763–13.298) and remained elevated during remdesivir treatment. Compared to the pre-exposure period, risks of ALI and AKI were not significantly higher in the first 2 days of remdesivir initiation (ALI: IRR = 1.261, 95% CI = 0.915–1.737; AKI: IRR = 1.261, 95% CI = 0.889–1.789) and between days 2 and 5 of remdesivir treatment (ALI: IRR = 1.087, 95% CI = 0.793–1.489; AKI: IRR = 1.152, 95% CI = 0.821–1.616).

Conclusion: The increased risks of AKI and ALI associated with intravenous remdesivir treatment for COVID-19 may be due to the underlying SARS-CoV-2 infection. The risks of AKI and ALI were elevated in the pre-exposure period, yet no such increased risks were observed following remdesivir initiation when compared to the pre-exposure period.

Introduction

Coronavirus disease 2019 (COVID-19) has posed an unprecedented challenge to nearly all governments worldwide, which are trying desperately to control the infection and mortality rate by means of vaccination and a variety of treatments. The pathogenesis of SARS-CoV-2 infection has been well-described.[1] Spike protein of coronaviruses binds with the receptor angiotensin-converting enzyme 2 (ACE2) expressed in alveolar cells, thereby promoting viral entry and utilising host cell machinery for replication with viral RNA-dependent RNA polymerase (RdRp).[2,3] Meanwhile, podocytes and proximal tubular cells in the kidney also express high levels of ACE2, which smay contribute to the development of acute kidney injury (AKI) upon SARS-CoV-2 infection.[3] While a remarkable drop in kidney function indicates the onset of acute tubular injury, the situation is often mild.[4] Another possible injury mechanism involves the immune system that triggers inflammation and immune cell infiltration, which play a critical role in tubular injury and thrombi.[4] A similar mechanism mediated by immune response and thrombosis could also be responsible for hepatocytes injury.[5] Meanwhile, hepatic injury is also noticed alongside elevated levels of liver enzymes, such as aspartate transaminase (AST) and alanine transaminase (ALT).[6] In addition, ACE2 is expressed at the highest level in cholangiocytes, followed by hepatocytes based on RNA sequencing data.[7] Therefore, hepatotoxicity is directly linked to viral infection despite variation in expression level.[8]

Remdesivir is an effective pharmaceutical option targeting the infection pathway and subsequent immune responses. It is a broad-spectrum antiviral monophosphoramidate prodrug that is metabolised in the liver to form remdesivir triphosphate; the metabolite is a nucleotide analogue that competes with ATP and interferes with RdRp activity, so viral RNA replication ceases to operate.[9–11] In this regard, this drug could trigger mitochondrial injury as it inhibits mammalian DNA and RNA polymerases.[9,11–15] This may lead to increased aminotransferase level in liver and mitochondrial injury in renal tubular cells, although action in the kidney may only occur with long-term treatment.[9,12,15] In addition, CYP3A4, which metabolises remdesivir in the liver, and hepatocytes transporters are susceptible to drug interactions with other agents, thus potentially causing liver damage.[11] Product label from FDA and EMA include increased transaminase level, bilirubin and creatinine as clinical implications, while the increase in liver enzymes is highlighted by FDA as a possible adverse side effect.[16,17] Despite these possible injurious mechanisms, the previous usage of remdesivir treating MER and EVD demonstrates a safe profile without significant renal adverse events.[9,18] Although cases of AKI and increased aminotransferase level have been reported for treating COVID-19, even among healthy volunteers, many randomised controlled studies have demonstrated limited adverse events with an acceptable safety profile.[9,11–15,19–21]

In brief, kidney and liver injury are reported shortly after remdesivir initiation in case studies,[9,22–24] but the exact injury mechanisms remain to be defined and investigated. Controlled trials may find remdesivir to be generally tolerable,[25–27] yet its safety data on AKI and acute liver injury (ALI) in the post-marketing real-world setting have not been published so far. With patients serving as their own control, this self-controlled case series (SCCS) study aims to estimate the risks of AKI and ALI with reference to remdesivir initiation among hospitalised COVID-19 patients who also had incident AKI or ALI.

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