Kidney Disorders as Serious Adverse Drug Reactions of Remdesivir in Covid-19: A Retrospective Case-Non case Study

Abstract

Remdesivir is a novel adenosine-like nucleotide analogue, representing the first drug approved for coronavirus disease 2019 (Covid-19), albeit an uncertain clinical relevance. In clinical trials and case series, acute kidney injury (AKI), including renal replacement, have been frequently reported. 1 , 2 Although causality is debatable, kidney injuries especially proximal tubular epithelial cell necrosis have also been observed in animal studies during remdesivir development. In order to provide additional information, we performed a pharmacovigilance analysis on the WHO global database of individual case safety reports (ICSRs), VigiBase (https://www.who-umc.org/vigibase/vigibase/). This database gathers spontaneous reports of suspected adverse drug reactions (ADR) from more than 130 countries, which makes it a very powerful tool to perform disproportionality analyses. 3 This approach, based on a case–non-case method, estimates whether an adverse event is differentially reported for a specific drug compared with other drugs. Among 1,565,117 reports registered until August 30th 2020, 5,532 concerned Covid-19 patients and have been included in this study. Of them, 434 (7.8%) cases were related to kidney disorders, including 327 (5.9%) reported with remdesivir. In remdesivir kidney disorder cases, 217 (66.3%) patients were male with a median age of 65 (IQR, 55-73) years (Suppl Table 1 ). Remdesivir was early discontinued with a median treatment duration of 3 (IQR, 1-4) days. In the vast majority of cases (316, 96.6%), no other drug was suspected in the onset of kidney disorders. Reactions were serious in 301 (92.0%) cases, with a fatal outcome for 15 (4.6%) patients. They were mainly AKI in 295 (90.2%) cases and tubular necrosis in 8 (2.4%) cases. Table 1 Reporting of kidney disorders in remdesivir users among COVID-19 patients, and their reporting odds-ratios within the WHO global safety database Kidney disorder cases∗ Non cases∗∗ ROR (95% CI) Primary analysis Remdesivir users 327 1526 7.2 (5.7-9.0) Other drug users 107 3572 1 (Reference) Sensitivity analysis restricted to severe to critical COVID-19 patients Remdesivir users 327 1526 3.7 (2.6-5.4) Dexamethasone, sarilumab or tocilizumab users 34 591 1 (Reference) Sensitivity analysis restricted to serious kidney disorders ∗∗∗ Remdesivir users 301 1552 6.9 (5.4-8.7) Other drug users 101 3578 1 (Reference) Sensitivity analysis restricted to kidney disorders not including concomitant nephrotoxic drugs ∗∗∗∗ Remdesivir users 242 1611 6.1 (4.8-7.9) Other drug users 88 3591 1 (Reference) ROR, Reporting odds-ratio; 95% CI, 95% confidence interval. The case–non-case approach is similar to case–control method but for purpose of pharmacovigilance studies. Disproportionality in adverse drug reaction reporting between groups is expressed using reporting odds ratios (ROR) and their 95% confidence interval (95% CI). ROR is a ratio similar in concept to the odds ratio in case-control studies and corresponds to the exposure odds among reported cases of kidney disorders over the exposure odds among reported non-cases. A ROR over one suggests that kidney disorders are more frequently reported in remdesivir users compared with other drug users (i.e chloroquine, hydroxychloroquine, dexamethasone, lopinavir/ritonavir, sarilumab or tocilizumab users) among patients with Covid-19 (list of terms is provided in Supplemental data). Reports with remdesivir that also included any other drug mentioned above were further excluded (corresponding to 806 reports). To assess the robustness of the main analysis, we performed several sensitivity analyses. First, to take into account clinical patient status and intensive care unit settings, we further restricted the analysis to drugs specifically used in severe to critical Covid-19 patients (i.e. dexamethasone, sarilumab or tocilizumab). Second, we restricted the analysis (i) to serious kidney disorder cases only and (ii) to kidney disorder cases that did not included known concomitant nephrotoxic drugs. In sensitivity analyses, non-serious cases and, cases including concomitant nephrotoxic drugs, respectively, were considered as non-cases. ∗ Kidney disorder cases were individual case safety reports containing any reaction belonging to the kidney system as system organ class (SOC) according to the Medical Dictionary for Regulatory Activities (MedDRA, https://www.meddra.org/). ∗∗ Non cases were reports containing any other reaction. ∗∗∗ Serious cases were defined, according to the WHO, as the occurrence of death, life-threatening adverse event, inpatient hospitalisation or prolongation of an existing hospitalisation, significant disability or requirement of intervention to prevent any of these. ∗∗∗∗ List of concomitant or suspected nephrotoxic drugs is in Supplemental data Compared to the use of chloroquine, hydroxychloroquine, dexamethasone, sarilumab or tocilizumab, the use of remdesivir was associated with an increased reporting of kidney disorders (ROR, 7.2; CI 95% 5.7-9.0) (Table 1). The retrospective design of our pharmacovigilance analysis has several limitations especially under-reporting and residual confounders, including the role of Covid-19 in AKI occurrence. Nevertheless, sensitivity analyses showed similar results, especially when excluding other nephrotoxic drugs or when comparing to only drugs used in severe to critical Covid-19. Our findings, based on post-marketing real-life data from more than 5,000 Covid-19 patients, support that kidney disorders, almost exclusively AKI, represent a serious, early and potentially fatal ADR of remdesivir. These results are consistent with findings from another group. 4 Physicians should be aware of this potential risk and perform close kidney monitoring when prescribing remdesivir. Further data are needed to confirm that safety signal. Information Statement Information from VigiBase comes from a variety of sources, and the probability that the suspected adverse effect is drug-related is not the same in all cases. The information does not represent the opinion of the Uppsala Monitoring Center (UMC) or the World Health Organization and only reflects the authors’ opinion. Footnotes Contributors: LC and FM designed the study and drafted the paper. LC performed data extraction and statistical analysis. LHP, MT, BT and JMT critically reviewed the paper. All the authors approved the final version of the paper. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted. Competing interests: all authors have no relevant conflicts of interest to disclose. Funding: none Ethical approval: VigiBase is a fully de-identified database maintained by the UMC. According to VigiBase access rules, no specific ethical approval is needed. VigiBase access is granted to national and regional pharmacovigilance centers such our teams. Data sharing: aggregated data of spontaneous reports are available at http://www.vigiaccess.org/ Transparency statement: the corresponding author attests that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted.