The Association Between COVID-19 Medications and AKI: Analysis of the United States Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) and Bulk Kidney RNA-seq Data

Background: The FDA has approved three medications: Tocilizumab, Remdesivir, and Baricitinib, and issued several existing emergency use authorizations (EUAs) medications such as Paxlovid, REGEN_COV antibody et al., for the treatment of COVID-19. However, it has been observed that these medications may pose a risk factor for acute kidney injury (AKI). This study aims to investigate the potential association between the usage of these medications and the occurrence of AKI, as well as to elucidate the molecular mechanism underlying AKI induced by COVID-19 medications. Methods: The risk of AKI was compared among the COVID-19 patients receiving different medications. Pharmacovigilance data obtained from the FAERS was analyzed. Furthermore, we investigated whether the risk of AKI was influenced by factors such as sex, dosage, and potential drug-drug interactions among the medications used in COVID-19 patients. Additionally, we sought to identify genes and pathways associated with AKI that are regulated by COVID-19 medications, by comparing gene expression of kidneys from mice treated with COVID-19 medications to those from control mice. Whole kidney RNA-seq data was generated and analyzed. Results: We found that COVID-19 patients treated with remdesivir demonstrated a significantly higher risk of AKI compared to patients treated with other medications. Specifically, patients aged 50-70 or over 70 years were twice as likely to report AKI, compared to the <50 age demographic. Male patients prescribed remdesivir had a two-fold higher likelihood of reporting AKI compared to females. Additionally, patients who took vancomycin alongside remdesivir exhibited a 3.87-fold increased likelihood of reporting AKI as an adverse event (P<0.0001) when compared to patients prescribed vancomycin or remdesivir alone. Furthermore, RNA-seq revealed that genes up-regulated by remdesivir included Edar, Per1, Gadd45g, Wnt7b, Wnt16, Agt, and Dusp15. The corresponding regulated pathways include Stress-activated MAPK cascade and JNK cascade. Conclusions: COVID-19 patients treated with remdesivir exhibited a higher risk of reporting AKI as an adverse event than patients prescribed other approved treatments for COVID-19 infection. This increased occurrence of AKI may be attributed to the activation of MAPK/JNK signaling pathway. Funding: NIDDK Support, Private Foundation Support