Remdesivir use for COVID-19 patients: Rates of serum creatinine levels to baseline or to upper limits to monitor postadministration renal function

Remdesivir use for COVID-19 patients: Rates of serum creatinine levels to baseline or to upper limits to monitor postadministration renal function | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Short Report Remdesivir use for COVID-19 patients: Rates of serum creatinine levels to baseline or to upper limits to monitor postadministration renal function Junichi Yoshida, Kenichiro Shiraishi, Tetsuya Kikuchi, Masao Tanaka This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2887144/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objectives: The incidence of remdesivir-induced renal dysfunction has not been investigated until now. The present study explored the clinical factors and laboratory data that predict remdesivir-induced renal dysfunction. The subjects were COVID-19 patients and we determined the endpoint as dialysis or death within 29 days. Background status parameters included (1) estimated glomerular filtration rate 1.5, (3) SCr ratios to upper limits > 1.5, (4) alanine aminotransferase ratios to upper limits > 5, (5) administration days, (6) sex, (7) age, (8) height, (9) weight, (10) dexamethasone use, and (11) SARS-CoV-2 vaccination. Results: In a total of 490 patients, a multivariate analysis showed that status (2) (odds ratio [OR] 8.342, 95% confidence interval [CI] 1.589-43.788, P=0.012) and status (7) (OR 7.620, CI 1.181-49.169, P=0.033) at 72 years or more were significant factors for remdesivir-induced renal dysfunction. To monitor renal function after remdesivir administration in COVID-19 patients, SCr ratios to baseline may work better than those to the upper limits. COVID-19 remdesivir renal function Common Terminology Criteria for Adverse Events creatinine Figures Figure 1 Introduction Remdesivir was developed for the treatment of Ebola virus disease, and it was repurposed to treat SARS-CoV-2 during the COVID-19 pandemic. Because of the drug itself, its metabolite, and/or its excipient, Gérard et al. [ 1 ] reported pharmacovigilance to prevent nephrotoxicity, which deserves a qualitative assessment. For the early detection of renal adverse events (AEs), we analyzed the time course of serum creatinine (SCr) levels using ratios to the baseline or to their upper limits as defined by the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 [ 2 ]. The clinical trial defined entry criteria including an estimated glomerular filtration rate (eGFR) > 30 ml/min/1.73 m 2 [ 3 ]. Regarding this criterion, Pettit et al [ 4 ] added that potential benefit may outweigh the risk but referred to its future validation. The present study explored the clinical factors and laboratory data that predict remdesivir-induced renal dysfunction. Methods The subjects were COVID-19 patients who had undergone remdesivir (Veklury; Gilead Sciences Inc., Foster City, California, United States) infusion from May 2020 through September 2022. Initially, a 5-day course of the agent was indicated for patients with decreased pulse oximetry to give for 5 days or more [ 3 ], but since March 2022, those with milder symptoms have been indicated for 3-day administration [ 5 ]. Considering the risk and benefit in COVID-19 patients, we selectively administered remdesivir to those with a decreased estimated glomerular filtration rate (eGFR) and/or with increased alanine aminotransferase (ALT). To define the postadministration day, we calculated Day X as follows: X = (Subject Day) - (Day of the first administration) On Day 0, a loading dose of 200 mg was given, and each subsequent day, 100 mg was administered. We retrospectively studied the time course of SCr levels, defining the endpoint as CTCAE Grade 4 or more on acute kidney injury, i.e., dialysis or all-cause deaths within 29 days. The levels of SCr, ALT and others were monitored on Days 0, 2, 4, and afterward. We assessed the following background status parameters: (1) eGFR 1.5, (3) SCr ratios to upper limits > 1.5 (Grade 2), (4) ALT ratios to upper limits > 5 (Grade 3), (5) remdesivir administration > = 4 days, (6) sex, (7) age, (8) height, (9) weight, (10) use of dexamethasone, and (11) number of SARS-CoV-2 vaccinations. We used Excel 2019 software (Microsoft Inc., Redmond, WA, USA) to generate line graphs depicting the time course of laboratory data. Because all the SCr ratios to baseline on Day 0 were 1, subsequent line graphs mimicked spider plots often used in oncologic studies to demonstrate the time course of tumor progression. This illustration allowed the detection of the highest data during 29 days, which were used for status (2), (3), and (4). We used software SPSS Statistics 28.0.1 software (IBM Inc., Armonk, NY, USA) for statistical analysis. For continuous variables, we performed receiver operating characteristic (ROC) analysis to determine cutoff values. The use of these data allowed subsequent univariate and multivariate regression analyses for the endpoint. Statistical significance was determined as P < 0.05. Results In a total of 490 patients (244 men and 246 women), cutoff values were 72 years for age, 3.5 days for remdesivir administration, and 0.5 times for SARS-CoV-2 vaccination (Table 1 ). Prior to the administration, 28 patients (5.7%) met the criteria for status (1) eGFR < 30 ml/min/1.73 m 2 , and 35 patients (7.1%) met the criteria for SCr levels described for status (3). Table 1 Univariate and multivariate analyses for the background factors to the endpoint of dialysis or death within 29 days (N = 15) of remdesivir administration (total N = 490). Patients showing increased alanine aminotransferase (ALT) levels showed no endpoints, thus at minimal risk (**). Note: *, statistical significance in multivariate analysis (P < 0.05); OR, odds ratio; CI, confidence interval; SCr, serum creatinine level; BL, ratio to the baseline; UL, upper limit; eGFR, estimated glomerular filtration rate; Vaccine, number of SARS-CoV-2 vaccination. Univariate analysis Multivariate analysis Factor Cutoff N OR 95% CI Lower 95% CI Upper P OR 95% CI Lower 95% CI Upper P SCr BLx1.5 13 29.188 8.107 105.077 < 0.001 8.342 1.589 43.788 0.012* SCr ULx1.5 48 9.262 3.197 26.834 < 0.001 4.130 0.547 31.208 0.169 eGFR 30 mL/min/1.73 m 2 28 6.833 2.026 23.049 0.002 1.168 0.140 9.720 0.885 Remdesivir 4 days 226 0.773 0.271 2.205 0.630 1.177 0.287 4.830 0.821 Age 72 years 256 6.206 1.385 27.799 0.017 7.620 1.181 49.169 0.033* Gender Male 244 0.664 0.233 1.894 0.444 0.229 0.026 1.993 0.182 Weight 53 kg 248 0.85 0.303 2.380 0.756 4.136 0.459 37.311 0.206 Height 164 cm 248 1.992 0.671 5.915 0.215 1.847 0.521 6.547 0.342 ALT ULx5 13 2.83x10 − 7 2.83x10 − 7 2.83x10 − 7 ** 3.55x10 − 7 3.55x10 − 7 3.55x10 − 7 ** Dexamethasone (+) 155 0.531 0.148 1.910 0.333 0.439 0.075 2.579 0.362 Vaccine 0.5 239 0.515 0.173 1.529 0.232 0.300 0.077 1.169 0.083 The endpoint numbered 15 patients, including one temporary dialysis patient and 14 deaths (2.9%). Among 13 patients (2.7%) with status (2), one developed renal failure with temporary dialysis while 4 others died. The peak Cr ratios were observed on Day 3. In contrast, 249 patients (50.8%) showed the highest ratio of 1 on Day 0 with a subsequent decrease (Fig. 1 ). Among 48 patients (9.8%) with status (3), one needed temporary dialysis while 6 patients died. A total of 14 patients (2.9%) died of COVID-19 within 29 days, but maintenance dialysis patients (N = 14) and those with renal transplantation (N = 3) survived. Patients with SCr ratios to the baseline > 1.5 accounted for 13 (2.7%) (Table 1 ), in whom the highest SCr values were 1.50 mg/dL or more. Patients with SCr ratios to the upper limit > 1.5 accounted for 48 (9.8%) more than in those with SCr ratios to the baseline (Table 1 ). A multivariate analysis showed significance in status (2) with an odds ratio [OR] of 8.342 and a 95% confidence interval [CI] of 1.589–43.788 (P = 0.012), in status (4) devoid of any endpoints, and in status (7) demonstrating an OR of 7.620 and a 95% CI of 1.181–49.169 (P = 0.033) at 72 years or more (Table 1 ). Discussion 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 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. 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. 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. Abbreviations AE, adverse event; SCr, serum creatinine; eGFR, estimated glomerular filtration rate; ALT, alanine aminotransferase; CTCAE, Common Terminology Criteria for Adverse Events; OR, odds ratio; CI, 95% confidence interval; ROC, receiver operating characteristics; AKI, acute kidney injury. Declarations Ethics approval and consent to participate: The Internal Review Board of Shimonoseki City Hospital issued approval and consent November 1, 2022, with the reference number 2022SCHEC-24. Therefore, informed consent was waived on the condition of posting the current study on the website, https://shimonosekicity-hosp.jp/content/100862529.pdf. All the authors confirm that all methods were performed in accordance with the relevant guidelines and regulations in accordance with the Declaration of Helsinki. Consent for publication: Not applicable. Availability of data and materials: The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Competing interests: The first author, Junichi Yoshida received a research fund from the clinical trials of Insmed Inc. and Shionogi Inc. Other authors, Kenichiro Shiraishi, Tetsuya Kikuchi and Masao Tanaka, have no COIs. Funding: Not applicable. Authors' contributions: J.Y. and K.S. wrote the draft of this manuscript. T.K. illustrated Figure 1. M.T. supervised the research conduct and the manuscript. All the authors read and approved the final manuscript. Acknowledgments: Not applicable. Authors' information (optional): Not applicable. References Gérard AO, Laurain A, Fresse A, Parassol N, Muzzone M, Rocher, et al. Remdesivir and Acute Renal Failure: A Potential Safety Signal From Disproportionality Analysis of the WHO Safety Database. Clin Pharmacol Ther. 2021;109:1021-4. doi: 10.1002/cpt.2145. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 Published: November 27, 2017 https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_5x7.pdf [accessed 25 November 2022]. Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC, et al. Remdesivir for the Treatment of Covid-19 - Final Report. N Engl J Med. 2020 Nov 5;383(19):1813-1826. doi: 10.1056/NEJMoa2007764. Pettit NN, Pisano J, Nguyen CT, Lew AK, Hazra A, Sherer R, et al. Remdesivir Use in the Setting of Severe Renal Impairment: A Theoretical Concern or Real Risk? Clin Infect Dis. 2021;73:e3990-5. doi: 10.1093/cid/ciaa1851. Gottlieb RL, Vaca CE, Paredes R, Mera J, Webb BJ, Perez G, et al. Early Remdesivir to Prevent Progression to Severe Covid-19 in Outpatients. N Engl J Med. 2022;386:305-15. doi: 10.1056/NEJMoa2116846. Wu B, Luo M, Wu F, He Z, Li Y, Xu T. Acute Kidney Injury Associated With Remdesivir: A Comprehensive Pharmacovigilance Analysis of COVID-19 Reports in FAERS. Front Pharmacol. 2022;13:692828. doi: 10.3389/fphar.2022.692828. Sunny S, Samaroo-Campbell J, Abdallah M, Luka A, Quale J. Is remdesivir safe in patients with renal impairment? Experience at a large tertiary urban medical center. Infection. 2022:1–6. doi: 10.1007/s15010-022-01850-7. Tan BWL, Tan BWQ, Tan ALM, Schriver ER, Gutiérrez-Sacristán A, Das P, et al. Long-term kidney function recovery and mortality after COVID-19-associated acute kidney injury: An international multi-centre observational cohort study EClinicalMedicine. 2023;55:101724 https://doi.org/10.1016/j.eclinm.2022.101724 Ito J, Kimura M, Toya T, Isozumi K, Kawaji A, Isozaki Y, et al. Remdesivir administration for Japanese COVID-19 patients undergoing maintenance hemodialysis: a retrospective observation with six case reports. Ren Replace Ther. 2022;8:14. doi: 10.1186/s41100-022-00404-9. Butt B, Hussain T, Jarrar M, Khalid K, Albaker W, Ambreen A, et al. Efficacy and Safety of Remdesivir in COVID-19 Positive Dialysis Patients. Antibiotics (Basel). 2022;11:156. doi: 10.3390/antibiotics11020156. Biancalana E, Chiriacò M, Sciarrone P, Khalid K, Albaker W, Ambreen, et al. Remdesivir, Renal Function and Short-Term Clinical Outcomes in Elderly COVID-19 Pneumonia Patients: A Single-Centre Study. Clin Interv Aging. 2021;16:1037-46. doi: 10.2147/CIA.S313028. Kayano T, Sasanami M, Kobayashi T, Ko YK, Otani K, Suzuki M, et al. Number of averted COVID-19 cases and deaths attributable to reduced risk in vaccinated individuals in Japan. Lancet Reg Health West Pac. 2022;28:100571. doi: 10.1016/j.lanwpc.2022.100571. Young B, Tan TT, Leo YS. The place for remdesivir in COVID-19 treatment. Lancet Infect Dis. 2021;21:20-21. doi: 10.1016/S1473-3099(20)30911-7. Rahimi MM, Jahantabi E, Lotfi B, Forouzesh M, Valizadeh R, Farshid S. Renal and liver injury following the treatment of COVID-19 by remdesivir. J Nephropathol. 2021;10:e10. doi: 10.34172/jnp.2021.10 Additional Declarations Competing interest reported. J. Yoshida has competing interests with Insmed Inc., Company. Other authors have no competing interests. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-2887144","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Short Report","associatedPublications":[],"authors":[{"id":197535105,"identity":"70f73489-fbad-44d6-a2f4-0c4a803e95d8","order_by":0,"name":"Junichi Yoshida","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA9UlEQVRIiWNgGAWjYHACNoYENgZmfgbGBgaGAiCfmVgtkg0gLQbEagEhgwMgtgERrjI43v7swYMyO3bjG8mNH34YHI42Z2dgfFzxC4+WM2fMDRLOJTOb3UhsluwxOJy7s5mB2fBsHx4tN3LYJBLbmEFa2hh4gFo2HGZgk2zswacl/RlQSz2z8YzENsY/xGlJMANqOcxsALILbkvDD9xaJM+cMZNIOHecWeLMw2ZpGYN0oBbGZsPGBtxa+IAhJvmjrDqZvz394cc3Fda5G84fPviw4Q9uLQoHIHQykhgwThnbcGuRh7rADk0cjy2jYBSMglEw4gAAu3VVL1V8JPQAAAAASUVORK5CYII=","orcid":"","institution":"Infection Control Committee, Shimonoseki City Hospital","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Junichi","middleName":"","lastName":"Yoshida","suffix":""},{"id":197535106,"identity":"6cc639aa-306b-4b25-9858-0c55c2095872","order_by":1,"name":"Kenichiro Shiraishi","email":"","orcid":"","institution":"Department of Clinical Immunology and Rheumatology / Infectious Disease, Kyushu University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Kenichiro","middleName":"","lastName":"Shiraishi","suffix":""},{"id":197535107,"identity":"520a608b-9578-44a7-8af1-6c64bec469cd","order_by":2,"name":"Tetsuya Kikuchi","email":"","orcid":"","institution":"Infection Control Committee, Shimonoseki City Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Tetsuya","middleName":"","lastName":"Kikuchi","suffix":""},{"id":197535108,"identity":"076feab9-9512-40c6-9b71-f09d61ef6c79","order_by":3,"name":"Masao Tanaka","email":"","orcid":"","institution":"Infection Control Committee, Shimonoseki City Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Masao","middleName":"","lastName":"Tanaka","suffix":""}],"badges":[],"createdAt":"2023-05-02 20:14:11","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2887144/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2887144/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":36721376,"identity":"3d278e8c-f519-44f0-a6c4-632bab360626","added_by":"auto","created_at":"2023-05-08 22:08:36","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":34558,"visible":true,"origin":"","legend":"\u003cp\u003eLine graph mimicking a spider plot for the 29-day course of serum creatinine ratios to the baseline of Day 0 or the day of remdesivir administration. The abscissa shows day numbers, and the ordinate shows the ratios. Patients showing a ratio of 1.5 or more are revealed at risk of dialysis or 29-day death. The software Excel (Microsoft Inc., Redmond, Washington, U.S.) allows samples up to 255; thus, the first 240 patients are depicted; the latter half of patients showed a similar trend.\u003c/p\u003e","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-2887144/v1/6efb151aeb3fd25fb05c027d.png"},{"id":36750133,"identity":"7a6f34a5-3b1b-47e1-806b-760e513047a5","added_by":"auto","created_at":"2023-05-09 16:44:33","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":451386,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2887144/v1/28103e15-dcf9-44df-b9d4-0d37668e3cf6.pdf"}],"financialInterests":"Competing interest reported. J. Yoshida has competing interests with Insmed Inc., Company.\nOther authors have no competing interests.","formattedTitle":"Remdesivir use for COVID-19 patients: Rates of serum creatinine levels to baseline or to upper limits to monitor postadministration renal function","fulltext":[{"header":"Introduction","content":"\u003cp\u003eRemdesivir was developed for the treatment of Ebola virus disease, and it was repurposed to treat SARS-CoV-2 during the COVID-19 pandemic. Because of the drug itself, its metabolite, and/or its excipient, Gérard et al. [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] reported pharmacovigilance to prevent nephrotoxicity, which deserves a qualitative assessment. For the early detection of renal adverse events (AEs), we analyzed the time course of serum creatinine (SCr) levels using ratios to the baseline or to their upper limits as defined by the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe clinical trial defined entry criteria including an estimated glomerular filtration rate (eGFR) \u0026gt; 30 ml/min/1.73 m\u003csup\u003e2\u003c/sup\u003e [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Regarding this criterion, Pettit et al [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] added that potential benefit may outweigh the risk but referred to its future validation. The present study explored the clinical factors and laboratory data that predict remdesivir-induced renal dysfunction.\u003c/p\u003e "},{"header":"Methods","content":"\u003cp\u003eThe subjects were COVID-19 patients who had undergone remdesivir (Veklury; Gilead Sciences Inc., Foster City, California, United States) infusion from May 2020 through September 2022. Initially, a 5-day course of the agent was indicated for patients with decreased pulse oximetry to give for 5 days or more [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], but since March 2022, those with milder symptoms have been indicated for 3-day administration [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Considering the risk and benefit in COVID-19 patients, we selectively administered remdesivir to those with a decreased estimated glomerular filtration rate (eGFR) and/or with increased alanine aminotransferase (ALT).\u003c/p\u003e\u003cp\u003eTo define the postadministration day, we calculated Day X as follows:\u003c/p\u003e\u003cp\u003eX = (Subject Day) - (Day of the first administration)\u003c/p\u003e\u003cp\u003eOn Day 0, a loading dose of 200 mg was given, and each subsequent day, 100 mg was administered.\u003c/p\u003e\u003cp\u003eWe retrospectively studied the time course of SCr levels, defining the endpoint as CTCAE Grade 4 or more on acute kidney injury, i.e., dialysis or all-cause deaths within 29 days. The levels of SCr, ALT and others were monitored on Days 0, 2, 4, and afterward.\u003c/p\u003e\u003cp\u003eWe assessed the following background status parameters: (1) eGFR \u0026lt; 30 ml/min/1.73 m\u003csup\u003e2\u003c/sup\u003e, (2) SCr ratios to baselines \u0026gt; 1.5, (3) SCr ratios to upper limits \u0026gt; 1.5 (Grade 2), (4) ALT ratios to upper limits \u0026gt; 5 (Grade 3), (5) remdesivir administration \u0026gt; = 4 days, (6) sex, (7) age, (8) height, (9) weight, (10) use of dexamethasone, and (11) number of SARS-CoV-2 vaccinations. We used Excel 2019 software (Microsoft Inc., Redmond, WA, USA) to generate line graphs depicting the time course of laboratory data. Because all the SCr ratios to baseline on Day 0 were 1, subsequent line graphs mimicked spider plots often used in oncologic studies to demonstrate the time course of tumor progression. This illustration allowed the detection of the highest data during 29 days, which were used for status (2), (3), and (4).\u003c/p\u003e\u003cp\u003eWe used software SPSS Statistics 28.0.1 software (IBM Inc., Armonk, NY, USA) for statistical analysis. For continuous variables, we performed receiver operating characteristic (ROC) analysis to determine cutoff values. The use of these data allowed subsequent univariate and multivariate regression analyses for the endpoint. Statistical significance was determined as P \u0026lt; 0.05.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eIn a total of 490 patients (244 men and 246 women), cutoff values were 72 years for age, 3.5 days for remdesivir administration, and 0.5 times for SARS-CoV-2 vaccination (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Prior to the administration, 28 patients (5.7%) met the criteria for status (1) eGFR\u0026thinsp;\u0026lt;\u0026thinsp;30 ml/min/1.73 m\u003csup\u003e2\u003c/sup\u003e, and 35 patients (7.1%) met the criteria for SCr levels described for status (3).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eUnivariate and multivariate analyses for the background factors to the endpoint of dialysis or death within 29 days (N\u0026thinsp;=\u0026thinsp;15) of remdesivir administration (total N\u0026thinsp;=\u0026thinsp;490). Patients showing increased alanine aminotransferase (ALT) levels showed no endpoints, thus at minimal risk (**). Note: *, statistical significance in multivariate analysis (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05); OR, odds ratio; CI, confidence interval; SCr, serum creatinine level; BL, ratio to the baseline; UL, upper limit; eGFR, estimated glomerular filtration rate; Vaccine, number of SARS-CoV-2 vaccination.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"11\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c7\" namest=\"c4\"\u003e \u003cp\u003eUnivariate analysis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c11\" namest=\"c8\"\u003e \u003cp\u003eMultivariate analysis\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFactor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCutoff\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003cp\u003eLower\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003cp\u003eUpper\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003cp\u003eLower\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003cp\u003eUpper\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSCr\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBLx1.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e29.188\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8.107\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e105.077\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e8.342\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1.589\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e43.788\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.012*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSCr\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eULx1.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9.262\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.197\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e26.834\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e4.130\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.547\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e31.208\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.169\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eeGFR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30 mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.833\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.026\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e23.049\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1.168\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.140\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e9.720\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.885\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRemdesivir\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 days\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e226\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.773\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.271\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.205\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.630\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1.177\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.287\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e4.830\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.821\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e72 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e256\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.206\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.385\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e27.799\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.017\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e7.620\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1.181\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e49.169\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.033*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e244\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.664\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.233\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.894\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.444\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.229\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.026\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1.993\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.182\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWeight\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e53 kg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e248\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.303\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.380\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.756\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e4.136\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.459\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e37.311\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.206\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeight\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e164 cm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e248\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.992\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.671\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5.915\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.215\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1.847\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.521\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e6.547\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.342\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eALT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eULx5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.83x10\u003csup\u003e\u0026minus;\u0026thinsp;7\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.83x10\u003csup\u003e\u0026minus;\u0026thinsp;7\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.83x10\u003csup\u003e\u0026minus;\u0026thinsp;7\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e**\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e3.55x10\u003csup\u003e\u0026minus;\u0026thinsp;7\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e3.55x10\u003csup\u003e\u0026minus;\u0026thinsp;7\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e3.55x10\u003csup\u003e\u0026minus;\u0026thinsp;7\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e**\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDexamethasone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(+)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e155\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.531\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.148\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.910\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.333\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.439\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.075\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e2.579\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.362\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVaccine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e239\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.515\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.173\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.529\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.232\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.300\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.077\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1.169\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.083\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe endpoint numbered 15 patients, including one temporary dialysis patient and 14 deaths (2.9%). Among 13 patients (2.7%) with status (2), one developed renal failure with temporary dialysis while 4 others died. The peak Cr ratios were observed on Day 3. In contrast, 249 patients (50.8%) showed the highest ratio of 1 on Day 0 with a subsequent decrease (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Among 48 patients (9.8%) with status (3), one needed temporary dialysis while 6 patients died.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eA total of 14 patients (2.9%) died of COVID-19 within 29 days, but maintenance dialysis patients (N\u0026thinsp;=\u0026thinsp;14) and those with renal transplantation (N\u0026thinsp;=\u0026thinsp;3) survived. Patients with SCr ratios to the baseline\u0026thinsp;\u0026gt;\u0026thinsp;1.5 accounted for 13 (2.7%) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e), in whom the highest SCr values were 1.50 mg/dL or more. Patients with SCr ratios to the upper limit\u0026thinsp;\u0026gt;\u0026thinsp;1.5 accounted for 48 (9.8%) more than in those with SCr ratios to the baseline (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eA multivariate analysis showed significance in status (2) with an odds ratio [OR] of 8.342 and a 95% confidence interval [CI] of 1.589\u0026ndash;43.788 (P\u0026thinsp;=\u0026thinsp;0.012), in status (4) devoid of any endpoints, and in status (7) demonstrating an OR of 7.620 and a 95% CI of 1.181\u0026ndash;49.169 (P\u0026thinsp;=\u0026thinsp;0.033) at 72 years or more (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe 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 [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], 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.\u003c/p\u003e \u003cp\u003eAs a drawback, SCr ratios to the baseline\u0026thinsp;\u0026gt;\u0026thinsp;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\u0026thinsp;\u0026gt;\u0026thinsp;1.5 was greater, making predictive power less than with SCr ratios to the baseline\u0026thinsp;\u0026gt;\u0026thinsp;1.5.\u003c/p\u003e \u003cp\u003eRegarding AKI, Wu et al. [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] 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 [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], however, reported that remdesivir was not associated with the development of AKI or hepatotoxicity in patients with an estimated creatinine clearance\u0026thinsp;\u0026lt;\u0026thinsp;30 mL/min.\u003c/p\u003e \u003cp\u003eIn contrast to AKI, Tan et al. [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] 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.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Additionally, Ito and others [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] described safe outcomes in six Japanese COVID-19 patients undergoing maintenance hemodialysis. For dialysis patients, Butt and colleagues [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] referred to the potential of remdesivir to shorten the recovery time. Similarly in our series, all the maintenance dialysis patients recovered without any sequelae.\u003c/p\u003e \u003cp\u003eOlder age was reported to carry high mortality among COVID-19 patients in Japan [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], which was revealed to be significant in our study. Biancalana and others [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] 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.\u003c/p\u003e \u003cp\u003ePrevious vaccination for SARS-CoV-2 contributed to reducing the risk of the endpoint, i.e., dialysis (N\u0026thinsp;=\u0026thinsp;1) and death (N\u0026thinsp;=\u0026thinsp;14) with marginal significance (P\u0026thinsp;=\u0026thinsp;0.083, Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). This finding reflected the efficacy of the vaccines, such as substantial reductions in the numbers of COVID-19 deaths by 67% in Japan [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Mortality during the use of remdesivir was reported to be 4% [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], comparable to our series of 2.9%. In addition, Rahimi and others [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] 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.\u003c/p\u003e \u003cp\u003eLimitations\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eOne 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.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eAnother 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.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eIn addition, all the patients were hospitalized because of the Japanese government\u0026rsquo;s policy of admitting COVID-19 patients of moderate grade or more. Internationally, however, admitted patients were of severe grade making global comparison difficult.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eWe 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.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAE, adverse event; SCr, serum creatinine; eGFR, estimated glomerular filtration rate; ALT, alanine aminotransferase; CTCAE, Common Terminology Criteria for Adverse Events; OR, odds ratio; CI, 95% confidence interval; ROC, receiver operating characteristics; AKI, acute kidney injury.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthics approval and consent to participate: The Internal Review Board of Shimonoseki City Hospital issued approval and consent November 1, 2022, with the reference number 2022SCHEC-24. Therefore, informed consent was waived on the condition of posting the current study on the website, https://shimonosekicity-hosp.jp/content/100862529.pdf. All the authors confirm that all methods were performed in accordance with the relevant guidelines and regulations in accordance with the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003eConsent for publication: Not applicable.\u003c/p\u003e\n\u003cp\u003eAvailability of data and materials: The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003eCompeting interests: The first author, Junichi Yoshida received a research fund from the clinical trials of Insmed Inc. and Shionogi Inc. Other authors, Kenichiro Shiraishi, Tetsuya Kikuchi and Masao Tanaka, have no COIs. \u003c/p\u003e\n\u003cp\u003eFunding: Not applicable.\u003c/p\u003e\n\u003cp\u003eAuthors\u0026apos; contributions: J.Y. and K.S. wrote the draft of this manuscript. T.K. illustrated Figure 1. M.T. supervised the research conduct and the manuscript. All the authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003eAcknowledgments: Not applicable.\u003c/p\u003e\n\u003cp\u003eAuthors\u0026apos; information (optional): Not applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eG\u0026eacute;rard AO, Laurain A, Fresse A, Parassol N, Muzzone M, Rocher, et al. Remdesivir and Acute Renal Failure: A Potential Safety Signal From Disproportionality Analysis of the WHO Safety Database. Clin Pharmacol Ther. 2021;109:1021-4. doi: 10.1002/cpt.2145.\u003c/li\u003e\n\u003cli\u003eU.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 Published: November 27, 2017 https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_5x7.pdf [accessed 25 November 2022].\u003c/li\u003e\n\u003cli\u003eBeigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC, et al. Remdesivir for the Treatment of Covid-19 - Final Report. N Engl J Med. 2020 Nov 5;383(19):1813-1826. doi: 10.1056/NEJMoa2007764. \u003c/li\u003e\n\u003cli\u003ePettit NN, Pisano J, Nguyen CT, Lew AK, Hazra A, Sherer R, et al. Remdesivir Use in the Setting of Severe Renal Impairment: A Theoretical Concern or Real Risk? Clin Infect Dis. 2021;73:e3990-5. doi: 10.1093/cid/ciaa1851.\u003c/li\u003e\n\u003cli\u003eGottlieb RL, Vaca CE, Paredes R, Mera J, Webb BJ, Perez G, et al. Early Remdesivir to Prevent Progression to Severe Covid-19 in Outpatients. N Engl J Med. 2022;386:305-15. doi: 10.1056/NEJMoa2116846. \u003c/li\u003e\n\u003cli\u003eWu B, Luo M, Wu F, He Z, Li Y, Xu T. Acute Kidney Injury Associated With Remdesivir: A Comprehensive Pharmacovigilance Analysis of COVID-19 Reports in FAERS. Front Pharmacol. 2022;13:692828. doi: 10.3389/fphar.2022.692828. \u003c/li\u003e\n\u003cli\u003eSunny S, Samaroo-Campbell J, Abdallah M, Luka A, Quale J. Is remdesivir safe in patients with renal impairment? Experience at a large tertiary urban medical center. Infection. 2022:1\u0026ndash;6. doi: 10.1007/s15010-022-01850-7. \u003c/li\u003e\n\u003cli\u003eTan BWL, Tan BWQ, Tan ALM, Schriver ER, Guti\u0026eacute;rrez-Sacrist\u0026aacute;n A, Das P, et al. Long-term kidney function recovery and mortality after COVID-19-associated acute kidney injury: An international multi-centre observational cohort study EClinicalMedicine. 2023;55:101724 https://doi.org/10.1016/j.eclinm.2022.101724\u003c/li\u003e\n\u003cli\u003eIto J, Kimura M, Toya T, Isozumi K, Kawaji A, Isozaki Y, et al. Remdesivir administration for Japanese COVID-19 patients undergoing maintenance hemodialysis: a retrospective observation with six case reports. Ren Replace Ther. 2022;8:14. doi: 10.1186/s41100-022-00404-9.\u003c/li\u003e\n\u003cli\u003eButt B, Hussain T, Jarrar M, Khalid K, Albaker W, Ambreen A, et al. Efficacy and Safety of Remdesivir in COVID-19 Positive Dialysis Patients. Antibiotics (Basel). 2022;11:156. doi: 10.3390/antibiotics11020156. \u003c/li\u003e\n\u003cli\u003eBiancalana E, Chiriac\u0026ograve; M, Sciarrone P, Khalid K, Albaker W, Ambreen, et al. Remdesivir, Renal Function and Short-Term Clinical Outcomes in Elderly COVID-19 Pneumonia Patients: A Single-Centre Study. Clin Interv Aging. 2021;16:1037-46. doi: 10.2147/CIA.S313028. \u003c/li\u003e\n\u003cli\u003eKayano T, Sasanami M, Kobayashi T, Ko YK, Otani K, Suzuki M, et al. Number of averted COVID-19 cases and deaths attributable to reduced risk in vaccinated individuals in Japan. Lancet Reg Health West Pac. 2022;28:100571. doi: 10.1016/j.lanwpc.2022.100571. \u003c/li\u003e\n\u003cli\u003eYoung B, Tan TT, Leo YS. The place for remdesivir in COVID-19 treatment. Lancet Infect Dis. 2021;21:20-21. doi: 10.1016/S1473-3099(20)30911-7. \u003c/li\u003e\n\u003cli\u003eRahimi MM, Jahantabi E, Lotfi B, Forouzesh M, Valizadeh R, Farshid S. Renal and liver injury following the treatment of COVID-19 by remdesivir. J Nephropathol. 2021;10:e10. doi: 10.34172/jnp.2021.10 \u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"COVID-19, remdesivir, renal function, Common Terminology Criteria for Adverse Events, creatinine","lastPublishedDoi":"10.21203/rs.3.rs-2887144/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2887144/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjectives:\u003c/strong\u003e The incidence of remdesivir-induced renal dysfunction has not been investigated until now. The present study explored the clinical factors and laboratory data that predict remdesivir-induced renal dysfunction.\u003c/p\u003e\n\u003cp\u003eThe subjects were COVID-19 patients and we determined the endpoint as dialysis or death within 29 days. Background status parameters included (1) estimated glomerular filtration rate \u0026lt; 30 ml/min/1.73 m\u003csup\u003e2\u003c/sup\u003e, (2) serum creatinine (SCr) ratios to baseline \u0026gt; 1.5, (3) SCr ratios to upper limits \u0026gt; 1.5, (4) alanine aminotransferase ratios to upper limits \u0026gt; 5, (5) administration days, (6) sex, (7) age, (8) height, (9) weight, (10) dexamethasone use, and (11) SARS-CoV-2 vaccination.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e In a total of 490 patients, a multivariate analysis showed that status (2) (odds ratio [OR] 8.342, 95% confidence interval [CI] 1.589-43.788, P=0.012) and status (7) (OR 7.620, CI 1.181-49.169, P=0.033) at 72 years or more were significant factors for remdesivir-induced renal dysfunction. To monitor renal function after remdesivir administration in COVID-19 patients, SCr ratios to baseline may work better than those to the upper limits.\u003c/p\u003e","manuscriptTitle":"Remdesivir use for COVID-19 patients: Rates of serum creatinine levels to baseline or to upper limits to monitor postadministration renal function","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-05-08 22:08:31","doi":"10.21203/rs.3.rs-2887144/v1","editorialEvents":[{"type":"communityComments","content":1}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"044308ca-74f0-4eca-926b-f67d21eb3966","owner":[],"postedDate":"May 8th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2023-05-09T16:44:26+00:00","versionOfRecord":[],"versionCreatedAt":"2023-05-08 22:08:31","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-2887144","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2887144","identity":"rs-2887144","version":["v1"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}