CLINICAL RESEARCH Use and Safety of Remdesivir in Kidney Transplant Recipients With COVID-19 Anna Buxeda1,27, Carlos Arias-Cabrales1,27, María José Pérez-Sáez1, Judit Cacho2, Sheila Cabello Pelegrin3, Edoardo Melilli4, María José Aladrén5, Cristina Galeano6, Inmaculada Lorenzo7, Auxiliadora Mazuecos8, Isabel María Saura9, Antonio Franco10, María del Carmen Ruiz-Fuentes11, Luis Alberto Sánchez-Cámara12, Orlando Siverio13, María Luisa Martin14, Elena González-García15, Verónica López16, Paloma Leticia Martin-Moreno17, Iñigo Moina18, Esperanza Moral Berrio19, Francesc Moreso20, José María Portolés21, Raquel Santana-Estupiñán22, Sofía Zárraga23, Cristina Canal24, Emilio Sánchez-Álvarez25, Julio Pascual1,28 and Marta Crespo1,28; for the Spanish Society of Nephrology COVID-19 Group26 1 Department of Nephrology, Hospital del Mar, Institute Mar for Medical Research (IMIM), Red de Investigación Renal (RED- inREN) (RD16/0009/0013), Barcelona, Spain; 2Department of Nephrology, Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, Spain; 3Department of Nephrology, Hospital Universitario Son Espases, Palma de Mallorca, Spain; 4Department of Nephrology, Hospital Universitari de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain; 5Department of Nephrology, Hospital Universitario Miguel Servet, Zaragoza, Spain; 6Department of Nephrology, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain; 7Department of Nephrology, Hospital General de Albacete, Albacete, Spain; 8Department of Nephrology, Hospital Universitario Puerta del Mar, Cádiz, Spain; 9Department of Nephrology, Hospital Universitario Vírgen de la Arrixaca, El Palmar, Múrcia, Spain; 10Department of Nephrology, Hospital General Uni- versitario de Alicante, Alicante, Spain; 11Department of Nephrology, Hospital Universitario Virgen de las Nieves, Granada, Spain; 12Department of Nephrology, Hospital General Universitario Gregorio Marañón, Instituto de investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain; 13Department of Nephrology, Hospital Universitario Nuestra Señora de la Can- delaria, Tenerife, Spain; 14Department of Nephrology, Hospital Universitari Arnau de Vilanova, Lleida, Spain; 15Department of Nephrology, Hospital Universitario La Paz, Madrid, Spain; 16Department of Nephrology, Hospital Regional Universitario de Málaga and University of Málaga, Instituto de Investigación Biomédica de Málaga (IBIMA), Red de Investigación Renal (REDinREN) (RD16/0009/0006), Málaga, Spain; 17Department of Nephrology, Clínica Universidad de Navarra, Navarra Institute for Health Research (IdiSNA), Pamplona, Spain; 18Department of Nephrology, Hospital Universitario de Basurto, Bilbao, Spain; 19 Department of Nephrology, Hospital General Universitario de Ciudad Real, Ciudad Real, Spain; 20Department of Nephrology, Hospital Universitari Vall d’Hebrón, Barcelona, Spain; 21Department of Nephrology, Hospital Universitario Puerta de Hierro, Majadahonda, Madrid, Spain; 22Department of Nephrology, Hospital Universitario de Gran Canaria Doctor Negrín, Las Palmas de Gran Canaria, Spain; 23Department of Nephrology, Hospital Universitario de Cruces, Barakaldo, Bilbao, Spain; 24Department of Nephrology, Fundació Puigvert, Barcelona, Spain; and 25Department of Nephrology, Hospital de Cabueñes, Gijón, Spain Introduction: Remdesivir has demonstrated antiviral activity against coronavirus, shortening the time to recovery in adults hospitalized with moderate/severe COVID-19. Severe adverse events such as acute kidney injury have been reported. Scant data are available on the use and safety of remdesivir in kidney transplant recipients. Methods: We present a multicenter cohort study of 51 kidney transplant recipients with COVID-19 treated with remdesivir. Outcomes and safety were assessed. Results: Mean age at diagnosis was 60 years, with a median time since kidney transplant of 4.5 years. Mean time since admission to remdesivir was 2 days. Twenty-eight patients (54.9%) required mechanical ventilation (19 noninvasive). Mortality was 18.9% and markedly higher if aged $65 years (45% vs. 3.2% in younger patients). Acute kidney injury was present in 27.7% of patients, but was diagnosed in 50% before treatment. No patients required remdesivir discontinuation because of adverse events. We did not find significant hepatoxicity or systemic symptoms resulting from the drug. 27 Correspondence: Julio Pascual and Marta Crespo, Nephrology AB and CA-C are co-first authors. Department, Hospital del Mar, Passeig Marítim, 25-29, 08003 28 JP and MC are co-senior authors. Barcelona, Spain. E-mails: julpascual@gmail.com and mcrespo@ psmar.cat Received 17 April 2021; revised 16 June 2021; accepted 21 June 2021; published online 6 July 2021 26 Members of the Spanish Society of Nephrology COVID-19 Group are listed in the Supplementary Information. Kidney International Reports (2021) 6, 2305–2315 2305 CLINICAL RESEARCH A Buxeda et al.: Remdesivir in KT Recipients With COVID-19 Conclusion: In our cohort of kidney transplant recipients, remdesivir was well tolerated and safe in renal and hepatic toxicity, but randomized trials are needed to assess its efficacy. Kidney Int Rep (2021) 6, 2305–2315; https://doi.org/10.1016/j.ekir.2021.06.023 KEYWORDS: acute kidney injury; immunosuppression; kidney transplantation; remdesivir; SARS-CoV2l ª 2021 International Society of Nephrology. Published by Elsevier Inc. This is an open access article under the CC BY- NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). ince March 11, 2020, Spain and many other AKI and CKD, including those on RRT.24,25 Assessment S countries have seen a 3-wave pattern in reported cases of SARS-CoV2 COVID-19.1,2 As of February 17, of drug-induced nephrotoxicity is particularly chal- lenging because COVID-19 also bears frequent renal 2021, more than 3,105,000 cases of COVID-19 and complications.26–28 55,000 deaths due to the infection have been reported Remdesivir has scarcely been used in KT patients in Spain, being the seventh most affected country.1,3 with COVID-19.5,7,24,29 KT recipients have only 1 Kidney transplant (KT) recipients appear to be at functioning kidney most of the time, with reduced notable high risk for critical COVID-19 illness due to eGFR compared with the general population, and long-term immunosuppression, age, coexisting comor- frequently receive calcineurin inhibitors, which bidities, and frequent contact with health care facil- compromise the glomerular blood flow. Minimal data ities.4–8 Among 35,183 prevalent KT recipients in are currently available on the use and safety of Spain,9 almost 1700 cases of COVID-19 have been re- remdesivir in this at-risk population.24 Here, we pre- ported by the Spanish Society of Nephrology (S.E.N.) sent the results of a Spanish multicenter study gath- registry. This results in a global incidence of 4.8%,10 ering data of 51 KT recipients treated with remdesivir similar to 6.1% reported in the general population.1 for COVID-19. Their outcomes, safety profile, renal Treatment for COVID-19 has been a matter of debate impairment, and tacrolimus interaction were assessed. during the pandemic spread, including both antiviral and anti-inflammatory drugs.11–17 Remdesivir is a METHODS prodrug of an adenosine analog that has demonstrated Patients antiviral activity against a broad range of RNA virus A Spanish registry comprising dialysis and KT patients families, including coronaviruses. This drug has shown with a confirmed diagnosis of COVID-19 started on nanomolar in vitro activity against SARS-CoV2 in hu- March 18, 2020 (S.E.N. COVID-19 registry), as previ- man airway epithelial cells and clinical and virologic ously described.10 Only patients diagnosed with posi- efficacy in a primate model.18 Some clinical trials tive reverse-transcriptase polymerase chain reaction showed that remdesivir was superior to placebo in assay of a specimen collected on a nasopharyngeal swab shortening the time to recovery in adults hospitalized or bronchoalveolar lavage were included. Of these, KT with COVID-19.16,17 patients who received remdesivir treatment were However, all remdesivir trials have excluded pa- included in this study. Until February 1, 2021, 48 were tients with severe acute kidney injury (AKI), chronic identified to have received remdesivir in 26 different kidney disease (CKD) with an estimated glomerular hospitals. Each center was contacted and invited to filtrate rate (eGFR) <30 ml/min per 1.73 m2, or those on participate in the study by completing an expanded renal replacement therapy (RRT). There are concerns retrospective database with more detailed data from about the potential toxicity of remdesivir in patients this cohort. Twenty-four centers completed the data- with renal impairment related both to dose-dependent base for 43 patients, and 8 additional patients were direct tubular damage produced by remdesivir in included, resulting in a final number of 51 patients. experimental studies and the potential accumulation of The median time of follow-up since the onset of its sulfobutylether-b-cyclodextrin (SBECD) carrier.19 symptoms to recovery/death was 25 days (interquartile The most common adverse events described in pa- range [IQR], 16–35 days) and to the end of follow-up tients treated with remdesivir are increased hepatic was 49 days (IQR, 34–68 days). enzymes, diarrhea, rash, renal impairment, and hypo- tension.20,21 Particularly, the development of AKI has Data Collection and Definitions been described in up to 22.8% of patients treated with The characteristics and variables included in the remdesivir.21,22 Nevertheless, randomized clinical trials COVID-19 registry have been previously reported.8,30 presented a comparable incidence of AKI between Added in the expanded database were more specific remdesivir and placebo.16,23 Moreover, recent studies and detailed data regarding demographics (recipient reported remdesivir was well tolerated in patients with age, sex, race, and comorbidity), time after KT, time 2306 Kidney International Reports (2021) 6, 2305–2315 A Buxeda et al.: Remdesivir in KT Recipients With COVID-19 CLINICAL RESEARCH between onset of symptoms and admission, epidemic Table 1. Baseline characteristics among kidney transplant waves, respiratory situation, including arterial partial recipients with COVID-19 infection who received remdesivir pressure of arterial oxygen/fraction of inspired oxygen Variablesa All (N [ 51) ratio (PaO2/FIO2) index, acute respiratory distress syn- Baseline characteristics drome, oxygen saturation by pulse oximetry, or Recipient age, y 60  13 Recipient age $65 y 20 (39.2) pneumonia demonstrated by X-ray imaging; remdesivir Male sex 33 (65.7) treatment (days of remdesivir treatment, remdesivir White race 36 (70.6) dose), inflammatory markers, maintenance immuno- Underlying diabetic kidney disease 8 (15.7) suppressive treatment at admission, tacrolimus blood First kidney transplant 43 (84.3) levels, kidney function, liver parameters, and adverse History of smoking 5 (9.8) events. These variables were chosen based on their Comorbidities Lung disease 6 (11.8) clinical relevance and previous results obtained from Ischemic heart disease 7 (13.7) our group. Arterial hypertension 42 (82.4) Criteria for remdesivir treatment were based on the Diabetes mellitus 16 (31.4) protocol of each hospital, although all patients pre- History of cancer 7 (13.7) sented with one of the following: requirement of sup- Obesity (body mass index >30 kg/m2) 12 (23.5) plemental oxygen, rapidly progressive acute ACEi or ARB treatment 17 (33.3) Immunosuppressive therapy respiratory distress syndrome (defined as PaO2/FIO2 Thymoglobulin induction 15 (29.4) index <300) and/or bilateral pneumonia with rapidly Calcineurin inhibitor 48 (94.1) increased levels of inflammatory markers, such as C- Tacrolimus 44 (86.3) reactive protein (CRP), interleukin-6, D-dimer, ferritin, Prednisone 43 (84.3) or lactic acid dehydrogenase. Most patients had given Mycophenolate 42 (82.4) mTOR inhibitor 7 (13.7) oral informed consent before remdesivir administra- Baseline kidney function (before admission) tion. Remdesivir dose regimens were based on the Serum creatinine, mg/dl 1.4  0.4 protocol of each hospital. The most common dosing eGFR CKD-EPI, ml/min per 1.73 m2 53.8  18.7 regimen was 200 mg on day 1, followed by 100 mg on eGFR <30 ml/min per 1.73 m2 2 (3.9) days 2 through 5. At admission Obesity was defined as body mass index >30 kg/m2. Time from KT to COVID-19 diagnosis, y 4.5 (1–10.5) Time from KT #6 months 9 (17.6) The immunosuppression regimen corresponds to that received at the time of COVID-19 diagnosis. AKI was ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; eGFR CKD-EPI, estimated glomerular filtrate rate calculated using Chronic Kidney Disease defined following Kidney Disease: Improving Global Epidemiology Collaboration equation; KT, kidney transplantation, mTOR, mammalian Outcomes criteria for stage 1, stage 2, and stage 3.31 The target of rapamycin. a Data correspond to clinical characteristics before hospital admission. last serum creatinine (SCr) value before admission was Continuous data are presented as mean  SD or median (interquartile range) and categorical data as n (%). considered as the baseline to assess the incidence of AKI. Drug-induced liver injury was defined according to a grading system developed by the Drug-Induced levels before admission to assess the incidence and Liver Injury Network. Grade 1 or mild was defined outcomes of AKI and tacrolimus levels variability. as raised serum alanine aminotransferase (ALT) or Outcomes were assessed as COVID-19–related mor- alkaline phosphatase levels, or both, but total serum tality or recovery until February 10, 2021. Recovery bilirubin <2.5 mg/dl and no coagulopathy (interna- was defined as hospital discharge or clinical judgment tional normalized ratio <1.5). No patients presented based on 1 negative reverse-transcriptase polymerase severity grades 2 to 5.32 Respiratory symptoms chain reaction result and symptom resolution. Time to included cough, sneezing, and rhinorrhea but excluded events was defined as days from COVID-19 diagnosis to dyspnea, which was collected separately. Respiratory death or recovery. status was recorded through PaO2/FIO2 when available The study was approved by the local Ethical Com- (n ¼ 21). If data to calculate the PaO2/FIO2 index were mittee at Hospital del Mar, Barcelona, Spain, and con- missing, oxygen saturation by pulse oximetry was ducted according to the guidelines as dictated by the considered (n ¼ 28). Declaration of Helsinki. All data were recorded Clinical follow-up and laboratory tests were anonymously. collected at 5 points: admission, when remdesivir was administered, early after remdesivir infusion (median, 2 Statistical Analysis days; IQR, 1–4 days), at discharge, and at early follow- Categorical data are summarized as counts and per- up after discharge (median, 28 days; IQR, 17–57 days). centages. According to their distribution, continuous Additionally, we collected the last SCr and tacrolimus data are expressed as mean and SD or median and IQR. Kidney International Reports (2021) 6, 2305–2315 2307 CLINICAL RESEARCH A Buxeda et al.: Remdesivir in KT Recipients With COVID-19 Table 2. Clinical and analytical features at admission for the COVID- recipient age at the time of the COVID-19 diagnosis was 19 episode 60  13 years. Most recipients were men (65.7%), All Caucasian (70.6%), and with a high prevalence of hy- Variable (N [ 51) pertension (82.4%). Diabetes mellitus was present in General data 31.4% of the cohort, ischemic heart disease in 13.7%, Wave and 11.8% had previous pulmonary disease. Tacroli- 1st wave (March–June, 2020) 3 (5.9) mus plus mycophenolate-based immunosuppression 2nd wave (July–December, 2020) 46 (90.2) 3rd wave (since January, 2021) 2 (3.9) was the most common therapy at admission (68.6% of Time between symptoms onset and admission, d 3 (2–5) recipients). Median time from KT to COVID-19 infec- Clinical features at COVID-19 diagnosis tion was 4.5 years, and 17.6% had received their Fever 40 (78.4) transplant within the last 6 months. Before admission, Dyspnea 36 (70.6) the mean SCr levels were 1.4  0.4 mg/dl and a mean Cough, expectoration, and/or rhinorrhea 40 (78.4) eGFR of 53.8  18.7 ml/min per 1.732. Gastrointestinal symptoms 19 (37.3) Respiratory situation PaFi, mm Hg (n ¼ 21) 300 (249–360) Clinical Characteristics and Laboratory Findings ARDS (PaFi <300) 10 (19.6) at COVID-19 Presentation Oxygen saturation, % (n ¼ 28) 93 (88.3–96.8) Table 2 summarizes clinical characteristics and labora- PaFi <300 or oxygen saturation #94% (n ¼ 45) 26 (51) tory data. The COVID-19 diagnosis in 90% of patients Pneumonia demonstrated by X-ray imaging 46 (90.2) occurred during the second wave. The median time Blood test at admission Lymphocytes, 103/ml (n ¼ 51) 0.9  1.2 between the onset of symptoms and hospital admission C-reactive protein, mg/L (n ¼ 50) 50.5 (7.6–109.5) was 3 days (IQR, 2–5 days). There was just 1 nosoco- Procalcitonin, ng/ml (n ¼ 38) 0.3 (0.1–0.8) mial SARS-CoV2 infection. The most common clinical Interlrukin-6, pg/ml (n ¼ 34) 42.8 (17.6–106.7) manifestations at admission were fever and respiratory Lactate dehydrogenase, IU/l (n ¼ 46) 295 (238.5–361.5) symptoms (78.4%), followed by dyspnea (70.6%) and Ferritin, ng/ml (n ¼ 45) 520 (295.5–1,134.5) gastrointestinal symptoms (37.3%). Chest X-ray imag- D-dimer, mg/l (n¼45) 667 (225–1,261) Serum creatinine, mg/dl (n ¼ 51) 1.68  0.7 ing showed pneumonia in 90% of patients. Twenty-six Bilirubin, mg/dl (n ¼ 45) 0.63 (0.4–0.88) patients (51%) presented acute respiratory distress Alanine aminotransferase, IU/l (n ¼ 49) 22 (14–31.5) syndrome or oxygen saturation #94% at admission. Aspartate aminotransferase, IU/l (n ¼ 45) 28 (18–33.5) Analytical parameters at admission showed lympho- ARDS, acute respiratory distress syndrome, PaFi, partial pressure of arterial oxygen/ penia and elevated inflammatory markers. fraction of inspired oxygen. Categorical data are presented as n (%) and continuous date as mean  SD or median (interquartile range). Treatment of COVID-19 Changes in immunosuppression strategy are displayed Univariate analyses were performed according to var- in Figure 1. Up to 86.3% of patients had at least 1 of iables normality, using c2 or Fisher exact tests to their immunosuppressants withdrawn at admission. analyze categorical variables, the Student t test for Mycophenolate or mammalian target of rapamycin in- continuous variables with normal distribution, and the hibitor withdrawal was the most frequent immuno- Mann-Whitney test U test for abnormal distribution suppression reduction strategy (49%), and only 4 data. Patient survival analysis according to age was patients maintained triple immunosuppressant therapy performed using Kaplan-Meier survival curves, during admission. Calcineurin inhibitor was with- applying the log-rank test. Statistical analysis was drawn in 39.6% of patients treated with this therapy. performed using SPSS 22.0 software (IBM, Armonk, Regarding anti–COVID-19 therapies, remdesivir was NY). A P value of <.05 was considered statistically administered at a median time of 2 days after admis- significant. We used GraphPad Prism 7 (GraphPad sion. Of the 15 patients who required intensive care Software, San Diego, CA) for data presentation. unit management, remdesivir was generally adminis- tered before admission, because the median time since hospital admission to intensive care unit was 4.5 days. RESULTS A trend toward a decrease in the mean duration of Patient Characteristics hospitalization was seen in the 27 patients in whom the During the observation period (March 12, 2020– drug was initiated within 48 hours of admission (12.5 February 1, 2021), 51 fully documented patients with days; IQR, 9–30 days) compared with 20 patients who COVID-19 had been treated with remdesivir and were received remdesivir beyond the first 48 hours after included in the study. Baseline characteristics of the admission (22.5 days; IQR, 15–34; P ¼ .07). Similarly, study population are summarized in Table 1. The mean the duration of oxygen therapy in the first group was 2308 Kidney International Reports (2021) 6, 2305–2315 A Buxeda et al.: Remdesivir in KT Recipients With COVID-19 CLINICAL RESEARCH Figure 1. Changes in immunosuppressive treatment after admission with SARS-CoV2 infection. (a) Changes in the number of immunosup- pressant drugs before hospital admission (left) and after admission (right). The number of immunosuppressant agents is color-coded. (b) Immunosuppressive withdrawal management after admission. CNI, calcineurin inhibitor; MPA, mycophenolate acid; mTORi, mammalian target of rapamycin inhibitor. slightly shorter (10 days [IQR, 5–23 days] vs. 16 days AKI was present in 27.7% of the cohort. Most pa- [IQR, 10–25 days], P ¼ .21). Nevertheless, we did not tients presented with AKI stage 1 (57.1%), and only 1 observe a lower mortality rate in patients who initiated patient required RRT, with complete recovery of renal the drug earlier (11.1% vs. 24%, P ¼ .21). The most function at discharge. Of 14 recipients with AKI, 8 frequent remdesivir regimen was 200 mg on day 1 and presented the peak SCr before the initiation of remde- 100 mg on days 2 through 5 (56%) (Figure 2). sivir, and therefore, renal function abnormalities could Most patients received combined treatment with not be attributable to the drug. The mean SCr levels at steroid pulses, and up to 70.6% received antibiotics remdesivir administration were 1.4  0.5 mg/dl, with a (other than azithromycin) due to confirmed or sus- mean eGFR of 57.5  18.8 ml/min per 1.73 m2. Only pected bacterial coinfections. Tocilizumab was admin- 8.5% of patients had eGFR <30 ml/min per 1.73 m2 istered in 14 patients, and most of them received the when remdesivir was initiated. AKI after remdesivir drug after remdesivir treatment, with a median time initiation happened in 11.7%. Of note, T-cell mediated from admission to the administration of tocilizumab of rejection developed in 1 patient, and another patient 5 days. Azithromycin, hydroxychloroquine, and rito- presented thrombotic microangiopathy. navir/lopinavir were less frequently used (Table 3). No patients required discontinuation of remdesivir therapy because of renal impairment. The dynamic profile of SCr after remdesivir treatment is detailed in General Outcomes and Safety End Points Figure 4a. Tacrolimus trough levels were analyzed Ninety percent of patients required supplemental ox- before and after remdesivir use in 22 patients who ygen. The respiratory failure led to noninvasive me- maintained the treatment during admission. We found chanical ventilation support in 19 patients (8 of them a significant decrease in tacrolimus levels after remde- outside an intensive care unit facility), and 9 required sivir treatment (6.9 ng/ml [IQR, 5.7–8.8 ng/ml] vs. 5.2 endotracheal intubation (Table 3). The fatality rate was ng/ml [IQR, 4.2–8.2 ng/ml], P ¼ .04), although the 18.9%, although markedly higher in recipients tacrolimus dose was reduced in 11 of 22 patients at aged $65 years (45% vs. 3.2%, P < .001) (Figure 3). admission. Kidney International Reports (2021) 6, 2305–2315 2309 CLINICAL RESEARCH A Buxeda et al.: Remdesivir in KT Recipients With COVID-19 Figure 2. Remdesivir regimens. Remdesivir dose regimens based on the protocol of each hospital. The most frequent remdesivir regimen was 200 mg (MG) on day 1 and 100 mg on days 2 through 5. Evolution of liver function is depicted in Figure 4b–d. aminotransferase [AST] and ALT levels) were observed Baseline liver function abnormalities (elevated aspartate in 4 patients before starting remdesivir. Only 2 patients were found to have newly occurring grade 1 elevation of AST/ALT, and liver function remained stable in 95.7% Table 3. Management and outcomes of kidney transplant recipients of patients after the drug administration. In the 4 pa- with COVID-19 infection who received remdesivir tients with raised baseline AST and ALT levels, All remdesivir therapy was not associated with worsening Variable (N [ 51) transaminitis. COVID-19 treatment Time since symptoms onset to remdesivir treatment, d 7 (5–9) We observed a significant decrease in CRP levels Time since admission to remdesivir treatment, d 2 (1–4) after treatment (53.6 mg/l [IQR, 9.1–114.7 mg/l] vs. 7.2 Azithromycin 6 (11.8) mg/l [IQR, 1.4–31.5 mg/l]), whereas other inflammatory Other antibiotics 36 (70.6) markers remained stable (Supplementary Table S1). Steroids (methylprednisolone bolus or dexamethasone) 49 (96.1) Finally, no rash or hypotension episodes were Time since admission to steroids treatment, d 1 (0–4) described after remdesivir administration in our Hydroxychloroquine 2 (3.9) Ritonavir/lopinavir 4 (7.8) cohort. Anakinra 6 (11.8) Tocilizumab 14 (27.5) DISCUSSION Time since admission to tocilizumab treatment, d 5 (4–7) Kidney function at remdesivir initiation Our study reports the largest cohort of KT recipients Serum creatinine, mg/dl 1.4  0.5 with COVID-19 treated with remdesivir. Outcomes of eGFR CKD-EPI, ml/min per 1.73 m2 57.5  18.8 eGFR <30 ml/min per 1.73 m2 4 (8.5) Outcomes and follow-up Supplemental oxygen 46 (90.2) ICU admission 15 (29.4) Time since hospital admission to ICU admission, d 4.5 (2.8–14.3) Noninvasive mechanical ventilation 19 (37.3) Endotracheal intubation 9 (17.6) AKIa 14 (27.5) AKI stage 1 8 (57.1) AKI stage 2 4 (28.6) Log Rank = 0.001 AKI stage 3 2 (14.3) AKI with renal replacement therapy need 1 (2) Time since hospital admission to SCr peak in patients with AKI, d 5 (0–8.5) < 65 31 31 29 26 20 8 Popula on years Time since remdesivir to SCr peak in patients with AKI, d 1 (4.5 to 8) at risk ≥ 65 20 20 17 15 12 5 years Acute rejection 1 (2) X-ray improvement after remdesivir (n ¼ 32) 13 (25.5) Figure 3. Patient survival according to age in kidney transplant AKI, acute kidney injury, eGFR CKD-EPI, estimated glomerular filtrate rate calculated recipient with COVID-19 treated with remdesivir. Kaplan-Meier curve using Chronic Kidney Disease Epidemiology Collaboration equation; ICU, intensive care shows mortality rates of kidney transplantation patients with COVID- unit; SCr, serum creatinine. a 19 according to recipient age (<65 years vs. $65 years). The median AKI stages 1, 2 and 3 outline the most severe AKI stage during hospital admission. Continuous data are presented as mean  SD or median (interquartile range) and time between the onset of symptoms and the end of follow-up was categorical data as n (%). 49 days (interquartile range, 34–68 days). 2310 Kidney International Reports (2021) 6, 2305–2315 A Buxeda et al.: Remdesivir in KT Recipients With COVID-19 CLINICAL RESEARCH a Serum creanine b Bilirubin 1 .5 2 .5 # 2 .0 1 .0 $ m g /d l 1 .5 m g /d l 1 .0 0 .5 0 .5 0 .0 0 .0 r m V V p m V V p -u -u a lC ad R D R D w ad R D R D w as at r st - ll o at I t- ll o B r C o fo I IL os fo C r p C r IL B I p I C B IL IL B B #P < .00 (vs. Basal Cr) p. ALL NS $P < .00 (vs. Basal Cr) c AST d ALT 50 60 ** 40 40 * 30 IU/l IU/l 20 20 10 0 0 p p m m V V V V -u -u ad ad D D D D ow ow R R R R at at t- t- ll ll T T os os fo fo S T L T p A p S L A T T A T A T S L S L A A A A p. ALL NS * P = .06 (vs ALT at admission) ** p = .02 (vs ALT at admission) Figure 4. Dynamic profile of kidney and liver function regarding COVID-19 infection evolution and remdesivir use. (a) Serum creatinine (Cr) levels at different time points: basal (preadmission), hospital admission (Adm), remdesivir administration (RDV), 72 hours after remdesivir, and early follow-up after discharge. Laboratory findings regarding liver function for (b) bilirubin, (c) aspartate aminotransferase (AST), and (d) alanine aminotransferase (ALT) between different time points: admission, remdesivir administration, 72 hours after remdesivir, and early follow- up after discharge. NS, not significant. 51 patients were analyzed, with an overall mortality of Developed initially as a possible treatment for the 18.9%, being markedly higher in recipients aged $65 Ebola virus disease, remdesivir has shown promising years. Most patients were diagnosed during the second results against SARS-CoV2 in reducing hospital stay wave. AKI developed in 27% of patients during the and mortality.15–17 However, a later study reported no study period, but only 11.7% was potentially attrib- effect on hospitalized patients with COVID-19, as uted to the drug. Remdesivir therapy was not with- indicated by overall mortality, initiation of ventilation, drawn because of renal impairment. We observed no and duration of hospital stay.33 The United States Food clinically significant ALT/AST increase after patients and Drug Administration and the European Medicines received the drug. Agency granted remdesivir emergency use during the The evolution of the pandemic in Spain has occurred first wave,34,35 but our study shows that remdesivir a 3-wave pattern in reported cases of COVID-19, with treatment in KT has been predominantly administered some differences in clinical features.1,2 Anti–COVID-19 during the second wave. therapies and epidemiologic characteristics of KT with The most common adverse events described in pa- SARS-CoV2 infection have changed between waves due tients treated with remdesivir are increased hepatic to a better knowledge of the disease.10 Anti–COVID-19 enzymes, diarrhea, rash, AKI, and hypotension.20,21 therapies, such as hydroxychloroquine or ritonavir/ Serious adverse events were reported in 24.6% of 532 lopinavir, are no longer used, whereas pulse steroid remdesivir-treated patients versus 31.6% of 516 pla- therapy has increased in consonance with the current cebo recipients in a randomized trial.16 The drug was scientific data10–14 as well as remdesivir. withdrawn early because of adverse events in 9.8% of Kidney International Reports (2021) 6, 2305–2315 2311 CLINICAL RESEARCH A Buxeda et al.: Remdesivir in KT Recipients With COVID-19 patients. No KT patient in our experience required function abnormalities attributable to the drug were remdesivir interruption due to adverse events. observed.24 The presumed toxicity in patients with renal More evidence is available from the use of remde- impairment is attributed to both remdesivir direct sivir in non-KT patients with AKI, CKD, or RRT, sug- tubular damage in experimental studies and SBECD gesting generally good tolerance.19,24,25,36,37 Aiswarya carrier accumulation. SBECD is a solubility-enhancing et al.25 analyzed 48 hemodialysis patients and showed agent predominantly excreted through glomerular no association with severe adverse events after 2 to 6 filtration. Studies in animals have associated SBECD doses of remdesivir were administered. They did not accumulation with renal tubule obstruction due to administer a loading dose of the drug because no evi- vacuolation at doses 50-fold higher than those typically dence of safety in patients with end-stage renal disease administered in humans. However, the short duration was available.25 of treatment (5–10 days) and relatively low concen- Other adverse effects reported after remdesivir use, tration of SBECD carrier used in COVID-19 treatment such as hypotension or rash,16,17 were not observed in (100 mg of lyophilized powder of remdesivir contains 3 our cohort. g of SBECD, and 100 mg solution of remdesivir contains As for immunosuppression, we found it of utmost 6 g of the carrier) would be far below SBECD recom- importance to assess tacrolimus blood trough levels mended safety thresholds of 250 mg/kg per day.19 Of variability in those patients treated with remdesivir note, most patients in our cohort received lyophilized who maintained the drug during admission. As an in- remdesivir powder. hibitor of cytochrome P450 3A4 in vitro, remdesivir Probably due to this potential nephrotoxicity, pa- could potentially interact with tacrolimus. However, its tients with CKD, including KT recipients, are under- capacity to be a perpetrator to clinically significant represented in the randomized studies with remdesivir. drug-drug interactions is limited by its rapid clearance For this reason, we aimed to evaluate the potential if kidney function is stable.38 Coadministration of toxicity related to this drug in these patients. Renal remdesivir with this nephrotoxic agent may increase impairment developed in 27% of our KT cohort, in line the plasma concentration of remdesivir metabolite, with previous reported evidence.5,7,30 However, nearly SBECD carrier, or tacrolimus levels. In our cohort, half of the patients in our cohort cases presented the tacrolimus blood trough levels were significantly lower peak SCr before remdesivir was initiated, including a after remdesivir treatment (6.9 vs. 5.2 ng/ml), but most case of acute rejection, and therefore, renal function patients underwent dose reduction at admission. More abnormalities could not be attributable to the drug. importantly, we found no tacrolimus accumulation in Of interest, all patients with AKI who survived the plasma due to remdesivir. recovered baseline graft function at the end of follow- Those patients who initiated remdesivir more than up. Antinori et al.21 described up to 22.8% of AKI in a 48 hours from admission showed a delayed discharge cohort of patients treated with remdesivir. Nonethe- (12.5 vs. 22.5 days since admission), which suggests less, as the authors postulated, the assessment of drug- that early treatment onset could be associated with a induced nephrotoxicity is particularly challenging better clinical response. Aiswarya et al.25 found early because COVID-19 also displays frequent renal com- initiation of remdesivir (within 48 hours of hospital plications, and randomized clinical trials have pre- admission) was associated with a decrease of 5.5 days in sented a comparable incidence of AKI between the mean duration of hospitalization.25 These results remdesivir and placebo.16,23,26–28 are consonant with what has been reported in the When we evaluated the potential hepatic toxicity, general population.15,16,39 only 2 patients were found to have newly occurring The mortality rate due to SARS-CoV2 infection in grade 1 elevations of AST/ALT. Moreover, remdesivir Spain has progressively decreased throughout the therapy was not associated with worsening trans- different waves. As of February 2020, the fatality rate aminitis in those patients with raised baseline AST and was 1.77% in the general population and 17% in the ALT levels. Similar results have been previously KT population.1,3,10 Impaired kidney function, immu- described in patients with AKI, CKD, or RRT.24,25 nosuppression, advanced age, pneumonia, and early The use and safety of remdesivir as part of COVID- post-KT period have been identified as risk factors for 19 management was previously reported in 16 pa- death.4,30,40–42 Our study cohort showed similar tients from 2 KT cohorts.24,29 Elec et al.29 analyzed 8 COVID-19–related mortality to that previously patients, with 6 of them presenting slightly decreased described in the overall cohort of KT by the S.E.N. eGFR upon discharge, which normalized within 1 registry, including both hospital and nonhospitalized month. Thakare et al.24 also included 8 KT patients infected patients. However, previously published with COVID-19 treated with remdesivir. No renal experience with remdesivir in COVID-19 patients with 2312 Kidney International Reports (2021) 6, 2305–2315 A Buxeda et al.: Remdesivir in KT Recipients With COVID-19 CLINICAL RESEARCH AKI, CKD, or RRT displayed higher mortality rates of is supported by a Spanish Society of Transplant 20% to 44%.24,25,36 Univariate analysis comparing scholarship. survivors and nonsurvivors in our cohort identified recipient age >65 years was associated with an AUTHOR CONTRIBUTIONS increased risk of death. In this group, the fatality rate AB, CA-C, MJP-S, JP, and MC designed the study, analyzed reached 45%. Multivariate analysis could not be per- the data, and drafted the manuscript. AB was the major formed due to the inherent limitations of the sample contributor in writing the manuscript. (AB, CA-C, MJP-S, size. JC, SC-P, EM, MJA, CG, IL, AM, IMS, AF, MCR-F, LAS-C, Our study has several limitations. Owing to its OS, MLM, EG-G, VL, PLM, IM, MEM, FM, JMP, RS-E, SZ, retrospective nature, some relevant clinical information CC, ES-A, JP, and MC revised the article, made substantial might be underreported, and residual confounders may contributions, and approved the final version of the be present. The small sample size and the lack of a manuscript. comparison group preclude establishing definitive as- sociations about safety or efficacy. Nonetheless, the SUPPLEMENTARY MATERIAL administration criteria were disease severity, and pa- Supplementary File (PDF) tients who received the drug presented a worse clinical Table S1. Dynamics of inflammatory markers regarding status than an eventual control group not receiving the remdesivir administration in KT recipients with COVID-19 drug. Therefore, to avoid selection bias, we did not STROBE statement include a contemporary or historical control group Supplementary Information because only a placebo-controlled trial can achieve this aim and very few KT patients with COVID-19 were left REFERENCES untreated when center protocols indicated remdesivir. 1. Informe no 66. Situación de COVID-19 en España a 17 de febrero Some patients received other anti–COVID-19 treatments de 2021. Equipo COVID-19. RENAVE. CNE. CNM (ISCIII). Accessed (i.e., tocilizumab), and therefore, we cannot discard the February 26, 2021. https://www.isciii.es/QueHacemos/Servicios/ potential influence of these therapies in outcomes. 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