Potential kidney damage associated with the use of remdesivir for COVID-19: analysis of a pharmacovigilance database

The U.S. Food and Drug Administration (FDA) has stated that the prescrip-tion of remdesivir should be cautious for patients with estimated glomerular filtration rate (eGFR) < 30 and some studies reported risk of adverse renal events. The available information on the renal safety profile for remdesivir is limited, thus we analyzed the renal and urinary adverse reactions attributed to remdesivir reported in a large open pharmacovigilance database. We obtained reports of remdesivir and other drugs used to treat COVID-19 (tocilizumab, hydroxychloroquine, lopinavir/ritonavir) registered by September 30 2020, from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS). We analyzed the reporting odds ratios (RORs) for reports of adverse renal and urinary events for remdesivir and other drugs. We found 2,922 reports with remdesivir registered in FAERS for COVID-19. Among these, 493 renal and urinary adverse effects (16.9%) were reported. The most frequent events were acute kidney injury (338; 11.6%), renal impairment (86; 2.9%), and renal failure (53; 1.8%). Versus hydroxychloroquine, lopinavir/ritonavir, or tocilizumab, the use of remdesivir was associated with an increased chance of reporting renal and urinary disorders regardless of gender and age of patients (2.53; 95%CI: 2.10-3.06). The ROR remained significant when we re-stricted the analysis to hydroxychloroquine (4.31; 95%CI: 3.25-5.71) or tocilizumab (3.92; 95%CI: 2.51-6.12). Our results reinforce this already reported signal, emphasizing that it could be extremely useful for health professionals who prescribe this new antiviral to treat COVID-19, mainly knowing its low efficacy.


Introduction
Remdesivir received authorization for emergency use from the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA) and the Brazilian Health Regulatory Agency (ANVISA) for treatment of severe coronavirus disease 2019 (COVID-19) 1,2,3 . Although several countries have approved the emergency use of remdesivir, the World Health Organization (WHO) does not recommend the use of this drug for the treatment of COVID-19. According to a large, simple, international, open-label randomized trial conducted by the WHO, remdesivir, hydroxychloroquine, and lopinavir did not reduce the mortality, the need for mechanical ventilation, and the duration of hospitalization 4,5 . Despite the lack of efficacy, these drugs continue to be used in the treatment of COVID-19 in some countries, such as Brazil 6 .
In addition to efficacy, the safety of the drugs used to treat COVID-19 is a concerning aspect. The remdesivir formulation contains sulfobutylether-beta-cyclodextrin (SBECD) as an excipient, which accumulates in patients with kidney dysfunction 7,8 . In repeated dose toxicity studies in animals, dosedependent kidney injury and/or reduced function was detected with remdesivir, however this was not observed in the phase I clinical studies 9,10 . Patients with an estimated glomerular filtration rate (eGFR) < 30 were excluded from reported clinical trials of remdesivir 11 , besides the FDA has stated that these patients should not receive remdesivir unless the potential benefit outweighs the potential risk 1 . Post-marketing retrospective studies have indicated that the use of remdesivir in patients with severe renal impairment is safe 12,13,14 . On the other hand, a review of published studies describing the treatment with remdesivir 15 reported that four out of 53 patients with severe COVID-19 developed renal impairment 16 . Acute kidney injury (AKI) was also reported in two studies 16,17 . A recent analysis of 363 notification with remdesivir and COVID-19 from VigiBase (the pharmacovigilance system of the WHO) has suggested that remdesivir may cause acute renal failure 18 .
The available information on the renal safety profile for remdesivir is still uncertain. Furthermore, concerning pharmacotherapy, COVID-19 itself may contribute to renal impairment. Between 20% and 40% of severe COVID-19 patients develop AKI and renal failure, mainly among those on mechanical ventilation due to a worse prognosis 19,20 .

Methods
The FAERS Public Dashboard is an open access database that includes reports of suspected adverse drug reactions (ADR) coordinated by the FDA. The reports for remdesivir and other drugs used in the treatment of COVID-19 (tocilizumab, hydroxychloroquine, and lopinavir/ritonavir) received by FAERS in September 30, 2020, were identified and characterized. Only reports describing its use to treat "COVID-19", "Coronavirus Infection", or SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) were selected. The occurrence of renal adverse events belonging to the "Renal and Urinary Disorders" organ system of the Medical Dictionary for Regulatory Activities (MedDRA; https:// www.meddra.org/) was analyzed.
A disproportionality analysis was performed, and the reporting odds ratios (RORs) and corresponding 95% confidence intervals (95%CI) for the associations were calculated 21 : (a) potential increased risk of reporting renal disorders with remdesivir compared with other drugs prescribed to treat COVID-19 (tocilizumab, hydroxychloroquine, and lopinavir/ritonavir), and (b) potential increased risk of reporting renal disorders with remdesivir versus other drugs. For these analyses, reports were excluded if more than one of the drugs analyzed was considered suspected of causing the adverse reaction. The ROR of a drug-ADR combination was defined as the ratio between proportions of reports containing the drug of interest in the "case" (reports containing the ADR of interest; renal Cad. Saúde Pública 2021; 37(10):e00077721 events) and in the "non-case" (reports containing other ADRs) group. All analyses were performed using counts of unique cases. An association was considered statistically significant when the limit of the 95%CI was greater (lower limit) or lower (upper limit) than 1.0.
For analysis of renal adverse reactions considering the groups of drugs (hydroxychloroquine, lopinavir/ritonavir, and tocilizumab combined and independent), a univariate logistic regression was performed from the estimate of the ROR and its 95%CI. Gender and age variables were considered to calculate the adjusted ROR in the logistic regression model, performed by the stepwise method, excluding the missing cases, both for the group with remdesivir and the other groups (hydroxychloroquine, lopinavir, tocilizumab combined and independent). The 5% significance level (p < 0.05) was considered for all statistical tests. The statistical analysis was conducted using the IBM SPSS Statistics program, version 25 (https://www.ibm.com/).

Discussion
The evidence about the safety profile of remdesivir used to treat COVID-19 in clinical settings is still uncertain. Thus, we searched in a large pharmacovigilance database, such as FAERS, to quickly identify signals confirmed with observational studies and a recent analysis of VigiBase indicated a higher highest risk of acute renal failure in patients with COVID-19 treated with remdesivir compared to tocilizumab, lopinavir/ritonavir and hydroxychloroquine (ROR = 20.3; 95%CI: 15.7-26.3) 18 .
The FAERS analysis in this study and the VigiBase analysis conducted by Gérard et al. 18 showed the increased chance of reporting renal disorders of different severity regardless of gender and age, even in a conservative analysis of the data, including only reports of adverse drug events associated with only one drug used to treat COVID-19. Thus, the FAERS result contributes to the strengthening of the renal disorder signal in patients with COVID-19 using remdesivir previously identified in VigiBase. Kidney damage could be one of the consequences of the infection with SARS-CoV-2 and the immunological cascade prompted by the virus. It could also be a consequence of these patients' comorbidities associated with COVID-19, by any means, the high proportion of renal and urinary reactions reported for patients using remdesivir are remarkable. Therefore, it generates a hypothesis to be confirmed in future studies and alerts health professionals to be aware of the potential nephrotoxic effect of remdesivir.
Renal adverse events may likely be associated with other nephrotoxic drugs used during the treatment of COVID-19, however in almost all reported cases, remdesivir was the only suspected drug and no other characteristic of the patients explained the observed difference. Despite the limitations of the disproportionality analyses of pharmacovigilance database reports, this method is well-known for identify unknown or poorly known adverse drug reactions, especially to new medicines or medicines used in situations different from those previously studied (signals). In fact, the EMA recently detected a safety signal about the use of remdesivir and the occurrence of kidney injury. The causal association has not yet been established and is under investigation 22 .
Spontaneous reporting systems (SRS), such as FAERS, are important to detect signals in the post-marketing surveillance, however SRSs have important limitations arising with underreporting, incomplete reporting, and duplicate reporting 23 . The sub-notification can overestimate the risk of an event with false-positive results. The quality of the report depends on the notifier's ability to recognize a possible association between medication use and the development of ADR. The event may sometimes be related to the patient's clinical condition (pre-existing diseases) or other medication not identified by the notifier as suspicious. Another recurring problem in the reports is the lack of information or the provision of incorrect information about the patient's characteristics (sex and age), comorbidities, and concomitant drugs that compromise the data analysis. There may also be notification of a similar incident by different reports (e.g., event notified by both the patient and by the physician), thus increasing the false positive rate 24 . Besides the limitations inherent in the SRSs themselves, we also observed limitations related to the study design. The interference of pre-existing comorbidities in the disproportionality analysis was not evaluated.
The signals identified with the SRS do not reflect the real incidence of ADR, since we found no information about exposure of the general population to the drug 23,25 . The signal has an exploratory character that serves as a starting point to emphasize early potential security problems and to instigate additional studies on these possible questions 26 .

Conclusion
Our findings emphasize the relevance of the EMA's alert and stressed the analysis of this suspected safety concern, especially if the ongoing clinical trials recommend the use of remdesivir to treat COVID-19. Including a much larger number of notifications, our analysis reinforces the signal identified in VigiBase in a previous study. Thus, even though we found limitations, the analysis of the notifications allows us to infer the need of monitoring the renal function during remdesivir treatment, particularly in patients with risk factors (such as advanced age), pre-existing renal impairment or those receiving combination therapy with nephrotoxic drugs.

Contributors
All authors contributed to the study design, data analysis and interpretation, writing, and critical review of the article.