The current study revealed that SCr ratios, rather than its absolute values, better predicted renal impairment and death after administration of remdesivir in patients with COVID-19. Even at the beginning of administration, the index with absolute SCr values showed a Grade 2 level at 7.1%, making follow-up monitoring difficult. The CTCAE Version 5.0 [2], however, defines another index of ratio to baseline levels; thus, we attempted to compare these two indices to detect renal impairment and, subsequently, to withhold further administration to prevent severe AEs.
As a drawback, SCr ratios to the baseline > 1.5 may have included patients with peak values remaining in the normal range. Among these patients, the maximum SCr values after remdesivir administration were 1.50 mg/dL or more, suggesting acute kidney injury (AKI) for all these patients. In contrast, the number of patients with SCr ratios to the upper limit > 1.5 was greater, making predictive power less than with SCr ratios to the baseline > 1.5.
Regarding AKI, Wu et al. [6] described that the mean time to this event was 4.91 days in the remdesivir group. Our series showed that peak SCr ratios were on Day 3, corresponding to their report. Sunny and others [7], however, reported that remdesivir was not associated with the development of AKI or hepatotoxicity in patients with an estimated creatinine clearance < 30 mL/min.
In contrast to AKI, Tan et al. [8] described that remdesivir contributed to improving renal function. In our series, Cr rates in 50.8% of patients showed a decreasing trend after Day 0 (Fig. 1). Additionally, Ito and others [9] described safe outcomes in six Japanese COVID-19 patients undergoing maintenance hemodialysis. For dialysis patients, Butt and colleagues [10] referred to the potential of remdesivir to shorten the recovery time. Similarly in our series, all the maintenance dialysis patients recovered without any sequelae.
Older age was reported to carry high mortality among COVID-19 patients in Japan [9], which was revealed to be significant in our study. Biancalana and others [11] described that, among elderly COVID-19 pneumonia patients, eGFR gain during such treatment was coupled with a better prognosis. Thus, elderly patients are likely to receive for remdesivir to circumvent viral pneumonia.
Previous vaccination for SARS-CoV-2 contributed to reducing the risk of the endpoint, i.e., dialysis (N = 1) and death (N = 14) with marginal significance (P = 0.083, Table 1). This finding reflected the efficacy of the vaccines, such as substantial reductions in the numbers of COVID-19 deaths by 67% in Japan [12]. Mortality during the use of remdesivir was reported to be 4% [13], comparable to our series of 2.9%. In addition, Rahimi and others [14] maintained that remdesivir may impair the liver function which may lead to fatality. Thus, we monitored ALT levels for 29 days when none of the highest values over Grade 2 were related to the endpoint.
Limitations
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One of the limitations was the all-cause mortality at the endpoint mostly due to worsening COVID-19. Because the all-cause mortality was difficult to distinguish between the respiratory failure and the combined effect of renal impairment, we defined deaths from all the causes.
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Another limitation was having been a retrospective study from a single institute. Since COVID-19 has been a novel infectious disease and, thus, remdesivir was repurposed to treat SARS-CoV-2 from Ebola virus, our retrospective study may have a place as real-world data.
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In addition, all the patients were hospitalized because of the Japanese government’s policy of admitting COVID-19 patients of moderate grade or more. Internationally, however, admitted patients were of severe grade making global comparison difficult.
We conclude that in COVID-19 patients with impaired renal function, monitoring the ratios of SCr from its baseline may augment monitoring of renal AE. The risk of older age may have reflected increased mortality in elderly individuals.