key: cord-0997397-8z59iz7p
authors: Estiverne, Christopher; Strohbehn, Ian A.; Mithani, Zain; Hirsch, Jamie S.; Wanchoo, Rimda; Goyal, Pranisha Gautam; Lee Dryden-Peterson, Scott; Pearson, Jeffrey C.; Kubiak, David W.; Letourneau, Alyssa R.; Bhattacharyya, Roby; Jhaveri, Kenar D.; Sise, Meghan E.
title: Remdesivir in patients with estimated glomerular filtration rate < 30mL/min/1.73m(2) or on renal replacement therapy
date: 2020-11-27
journal: Kidney Int Rep
DOI: 10.1016/j.ekir.2020.11.025
sha: c23fe0e2626582f6e5cccf45feb933b4cfc9324d
doc_id: 997397
cord_uid: 8z59iz7p

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As of October 2020, coronavirus disease 2019 (COVID-19) has caused over 43 million infections and over 1.1 million deaths worldwide. Remdesivir (GS-5734), a nucleotide prodrug that inhibits RNA-dependent RNA polymerase, accelerates recovery in patients with moderate to severe COVID-19 and was approved by emergency use authorization in May 2020 (1, 2) .

However, all studies of remdesivir have excluded patients with kidney impairment, using estimated glomerular filtration rate (eGFR) cutoffs of 30 or 50 mL/min/1.73m 2 , due to theoretical concerns about accumulation of remdesivir's active metabolite or its sulfobutylether-bcyclodextrin (SBECD) carrier (3) .

Acute kidney injury (AKI) occurs at a rate of 30-40% in hospitalized patients with COVID-19 (4). Chronic kidney disease (CKD) and end-stage renal disease (ESRD) are also common comorbidities in patients who develop severe COVID-19. There are currently no available data on the use of remdesivir in patients with eGFR < 30mL/min/1.73m 2 , and antiviral strategies are desperately needed in this population. We conducted a multi-center, observational, retrospective case series of adults with COVID-19 between May 7, 2020 and July 15, 2020 in order to describe changes in alanine aminotransferase (ALT) and serum creatinine during remdesivir therapy, and to report adverse events (AEs) attributed to remdesivir in hospitalized patients with COVID-19 who had eGFR <30mL/min/1.73m 2 or were receiving renal replacement therapy (RRT) at the time of starting remdesivir.

A total of 18 patients with eGFR < 30mL/min/1.73m 2 at the time of remdesivir initiation were included; baseline characteristics are shown in Table 1 . The median age was 68 years (IQR 55 -76), 50% were female, and 78% were from racial/ethnic minority groups. Medical comorbidities were common and 16 (89%) had documented CKD (eGFR < 60mL/min/1.73m 2 ) prior to the index hospitalization for COVID-19. Eleven patients were in intensive care and 9 J o u r n a l P r e -p r o o f were mechanically ventilated at the time of remdesivir initiation. At the time of remdesivir initiation, five patients were receiving RRT (two had ESRD, three had AKI). Among patients with eGFR < 30mL/min/1.73m 2 who were not on RRT at the time of starting remdesivir, five met criteria for AKI and eight had stable CKD.

Two patients developed alanine aminotransferase (ALT) > 5 times the upper limit of normal (Fig 1A) , both attributed to shock liver and not remdesivir. Other ALT abnormalities occurred, predominantly in critically ill patients, including 3 cases possibly or likely attributed to remdesivir use per study investigators (two grade 1, one grade 2, see Figure 1A ). Eight of 13 patients not requiring RRT at the time of remdesivir initiation experienced improved creatinine during remdesivir, while 5 worsened, including 4 who progressed to require RRT (Fig 1B) . In one case, study investigators determined the worsening creatinine was likely attributed to remdesivir.

Overall, treatment was well-tolerated, with few other AEs attributed to remdesivir, including two cases of hyperglycemia (each Grade 2) each on day 4 of treatment, one grade 3 anemia on day 3 of treatment, and burning at the infusion site on the final, fifth dose in one case. Five patients discontinued remdesivir early, only 2 of them due to AEs attributed to remdesivir (burning at IV site during the final dose and worsening kidney function); the remainder stopped due to improved clinical status (N=2) or patient preference (N=1). Overall 28-day mortality was 44% (8/18). Among patients requiring intensive care at the time of remdesivir initiation, 8 of 11 died. All 7 patients who were not requiring intensive care at baseline survived to 28 days.

In this multi-center case series, among 18 patients receiving remdesivir despite eGFR < 30 mL/min/1. The exclusion of patients with eGFR < 30mL/min/1.73m 2 from clinical trials has created an important gap in knowledge of safety data for remdesivir, as up to one in three critically ill patients with COVID-19 may have eGFR < 30mL/min/1.73m 2 (5) . Concerns about accumulation of the SBECD carrier should be allayed by the available safety data in patients with kidney failure treated with voriconazole, which uses the same carrier (3). The lyophilized powder formulation of remdesivir, which contains 3 grams of SBECD per 100mg dose compared to 6 grams in the liquid formulation, is preferred in patients with eGFR < 30mL/min/1.73m 2 (9) . In this series, 16 of 18 patients received the liquid formulation due to product availability, yet even this preparation still contains significantly less than the maximum recommended safety threshold of 250mg/kg/day of SBECD (3).

Our study has several important limitations. First, it is limited by the small number of cases; however, it includes a racially and ethnically diverse population. Second, lack of a comparison group and the retrospective ascertainment of AE relatedness are important limitations to our ability to draw conclusions about safety or efficacy. To avoid selection bias that we felt could be biased in favor of remdesivir, we did not include a contemporary or historical control group, as safety and efficacy can only be determined by a prospective placebocontrolled trial. Finally, although calculating eGFR in patients who have unstable creatinine is J o u r n a l P r e -p r o o f problematic, we included anyone whose creatinine most proximal to remdesivir initiation corresponded to an eGFR < 30mL/min1.73m 2 since, in practice, these are patients for whom treating clinicians will have to make the difficult decision about whether or not to initiate remdesivir.

This multi-center report including consecutive patients from four hospital systems is the first case series of remdesivir use in patients with eGFR < 30mL/min/1.73m 2 in the United States and highlights the urgent need for prospective studies in this common and high-risk population.

Methods (PDF). Supplementary information is available at KI Report's website. J o u r n a l P r e -p r o o f Figure 1A . Serum creatinine trends for the 13 patients not requiring renal replacement therapy (RRT) prior to starting remdesivir is shown in Figure 1B . Patients with end-stage kidney disease (2) or acute kidney injury on RRT (3) at the time of starting remdesivir are not shown in Figure 1B . Patients who initiated remdesivir in the intensive care unit (ICU) are shown in blue. Non-ICU patients (yellow) were receiving care on a medical floor or step-down unit. ALT and creatinine values recorded while on remdesivir treatment are shown with solid lines and the following 7 days are shown with dashed lines. Date of death is shown with a red X, hospital discharge is annotated by a solid circle. One patient died while taking remdesivir due to cardiac arrest and shock that was not attributed to remdesivir by the site investigator.

Remdesivir for the Treatment of Covid-19 -Preliminary Report

Effect of Remdesivir vs Standard Care on Clinical Status at 11 Days in Patients With Moderate COVID-19: A Randomized Clinical

Remdesivir in Patients with Acute or Chronic Kidney Disease and COVID-19

Acute kidney injury in patients hospitalized with COVID-19

Investigators S-C. Factors Associated With Death in Critically Ill Patients With Coronavirus Disease 2019 in the US

Presentation and Outcomes of Patients with ESKD and COVID-19

Outcomes of patients with end-stage kidney disease hospitalized with COVID-19

Epub 2020/10/20

An Antiviral for Treatment of COVID-19, in Healthy Subjects

Diabetes mellitus 9 (50) Coronary artery disease 5 (28) Transplant recipient 3 (17) Chronic obstructive pulmonary disease 2 (11) Liver disease/cirrhosis 1 (6) BMI (median (IQR)) 28.6 (24.9 -31) Baseline medications (n (%)) ACE-inhibitors 2 (11) Angiotensin II receptor blockers 2 (11) Immunosuppression 4 (22) Diuretics 5 (28) Statins 7 (39) RDV dosing regimen prescribed (n (%))** 5-day course 16 (89) 10-day course 2 (11) RDV doses actually administered (n (%)) 1 dose 2 (11) 3 doses 2 (11) 4 doses 2 (11) 5 doses 11 (61) 10 doses 1 (6) Days from symptom onset to RDV start (median (IQR)) 7 (3 -10.5) Adjuvant COVID-19 therapies used (n (%)) Tocilizumab 3 (17) Canakinumab 2 (11) Dexamethasone 4 (22) Methylprednisolone/prednisone 5 (28) Convalescent plasma 1 (6) Labs at admission (median (IQR)) Hemoglobin, g/dL 11.0 (9.9 -12.1) D-Dimer, ng/mL 2,196 (1,145 -3,750) Albumin, g/dL 3.4 (2.7 -3.8) C-reactive protein, mg/L 133.1 (59.3 -221.0) Location of admission (n (%)) Intensive care unit 11 (61) Hospital floor 7 (39) Oxygen support required at baseline (n (%)) Mechanical ventilation 9 (50) High-flow nasal cannula or non-rebreather 3 (17) Nasal cannula, ≤4L 6 (33) On vasopressors at RDV start (n (%)) 6 (33)

On ECMO at RDV start (n (%)) 1 (6) Table 1 . *Among the 8 patients meeting the definition of AKI, 6 also had baseline CKD **All patients receive 200mg IV bolus on day one followed by 100mg per day. Remdesivir solution was utilized in 16 cases and the powder formulation was utilized in 2 cases. Abbreviations: SD = standard deviation, CKD = chronic kidney disease, eGFR = estimated glomerular filtration rate, AKI = acute kidney disease, RRT = renal replacement therapy, ESRD = end-stage renal disease, BMI = body mass index, RDV = remdesivir, IQR = interquartile range, ECMO = extracorporeal membrane oxygenation.