Safety of Remdesivir in Patients With Acute Kidney Injury or CKD

Abstract

Patients with chronic kidney disease (CKD), especially those with end-stage renal disease (ESRD), are susceptible to the development of severe coronavirus disease 2019 (COVID-19), which is associated with high mortality.1Valeri A.M. Robbins-Juarez S.Y. Stevens J.S. et al.Presentation and outcomes of patients with ESKD and COVID-19.J Am Soc Nephrol. 2020; 31: 1409-1415Crossref PubMed Scopus (258) Google Scholar Apart from respiratory support depending upon the severity of the respiratory involvement, management of COVID-19 is largely supportive. Remdesivir is a nucleotide analog that inhibits viral RNA-dependent RNA polymerase (RdRp) and that was issued an emergency use authorization by the U.S. Food and Drug Administration in May 2020. The active metabolite of remdesivir is eliminated by the kidneys and can accumulate in patients with reduced estimated glomerular filtration rate (eGFR); moreover, the sulfobutylether-β-cyclodextrin (SBECD) carrier is known to accumulate in these patients. The largest clinical trial evaluating the use of this agent in COVID-19 excluded patients with stage 4 CKD or those requiring dialysis (i.e., eGFR <30 ml/min/1.73 m2).2Beigel J.H. Tomashek K.M. Dodd L.E. et al.Remdesivir for the treatment of Covid-19 – final report.N Engl J Med. 2020; 383: 1813-1826Crossref PubMed Scopus (5034) Google Scholar We aimed to report our single-center experience using remdesivir in patients with COVID-19 who had acute kidney injury (AKI) and CKD. One hundred fifty-seven patients with COVID-19 who were admitted to the intensive care unit or our nephrology high dependency unit between July 7 and September 22, 2020 had either AKI or CKD. Forty-six of 157 (29.3%) cases were treated with remdesivir. The median age of these patients was 53.1 years (range 15–84 years) and 30 (65.2%) were male. Renal diagnoses were ESRD in 16 (34.7%) and AKI in 30 (65.2%%) patients. Eight (17.4%) of 46 patients were recipients of live donor kidney transplants. Of 30 patients with AKI, 3 (6.5%), 2 (4.3%), and 25 (83.3%) patients had Kidney Disease: Improving Global Outcomes AKI stages 1, 2, and 3, respectively. Notably, all patients with stage 1 and 2 AKI were kidney transplant recipients. Table 1 shows the baseline characteristics of these cases. Comorbidities included hypertension in 35 (76%) patients, diabetes in 26 (56.5%) patients, coronary artery disease in 4 (8.7%) patients, nephrolithiasis in 3 (6.5%) patients, and HIV in 1 (2.2%) patient. Twelve (26%) patients were treated in the intensive care unit. At the time of initiation of remdesivir, oxygen requirements were as follows: noninvasive ventilation (n = 7), high flow nasal canula (n = 1), nonrebreathing mask (n = 11), face mask (n = 15), and nasal prongs (n = 12). Further in the course of illness, 9 (19.5%) patients required invasive mechanical ventilation.Table 1Baseline characteristics and patient response to remdesivir therapyCase no.Age/sexKidney disease (if AKI- KDIGO staging)Co-morbiditiesDuration of symptoms before remdesivir, daysO2 need before starting remdesivirSerum AST/ALT, IU/LDose of remdesivir, mgPatient outcome if still admitted (WHO ordinal score change)Before starting remdesivirPeak (if present)/within 48 hrs of cessation of therapy156/MESRDHTN, DM11NRBM, 6 L/min118/8126/25 (improved)600Died265/MESRDHTN, DM1HFNC24/1420/10600Died362/FAKI 3HTN, DM, CKD, nephrolithiasis3NIV13/16DeathaFurther trend of AST/ALT not available.500Died442/MAKI 3HTN, CKD10NRBM, 6 L/min39/14Day 5: 57/33, day 9: 19/21 (grade 1 AST elevation)600Discharged555/MESRDHTN4FM, 4 L/min20/2023/161200Discharged650/FAKI 3HTN, DM4FM, 8 L/min133/10114/30 (improved)600Discharged768/MAKI 3HTN, DM,CAD, CKD2NRBM, 6 L/min76/5643/36 (improved)500Died850/FAKI 3HTN, DM, CKD2FM, 10 L/min41/2736/23200Died950/MESRDDM3NRBM, 8 L/min69/6741/62 (persistent grade 1 ALT elevation)400Died1052/MAKI 3None7NIV101/6625/31 (improved)300Died1127/MAKI 3KTR, HTN, Beta thalassemia trait12NP, 4 L/min40/27Day 5: 39/57, day 9: 15/30 (grade 1 ALT elevation, improved at day 9)600Discharged1238/MAKI 3None4NIV35/4120/9600Discharged1349/MESRDHTN, DM, CAD5FM, 4 L/min33/2230/20600Discharged1444/FAKI 3HTN, CKD8NRBM, 6 L/min28/1427/11600Discharged1565/MAKI 3HTN, DM, CKD10NRBM 12 L/min20/12Day 3: 65/18 (grade 1 AST elevation), deathaFurther trend of AST/ALT not available.600Died1650/MAKI 3KTR, DM7NP, 4 L/min20/1132/8600Discharged1775/FESRDHTN, DM10NP, 6 L/min21/927/9600Admitted (4 to 3)1850/FAKI 2KTR, beta thalassemia trait10NP, 2 L/min21/948/39600Discharged1939/MAKI 3KTR, HTN, DM8NP, 2 L/min24/920/11600Discharged2043/FAKI 3HTN, CKD7NP, 4 L/min16/1120/13600Discharged2152/FESRDHIV, PTB4FM, 4 L/min116/7744/39 (improved)600Discharged2248/FAKI 1KTR3NRBM, 8 L/min23/1334/171100Discharged2360/MAKI 3HTN, DM, CKD8NIV34/2344/20600Died2415/FAKI 3CKD15NRBM, 8 L/min164/21948/113 (improved)500Discharged2538/FESRDHTN, CKD, PTB2FM, 4 L/min105/2759/19 (improved)600Discharged2646/FAKI 1KTR, HTN, DM8NP, 2 L/min27/3324/16600Discharged2784/MAKI 3HTN, DM, CKD15NP, 4 L/min22/3125/28600Discharged2853/MESRDHTN, DM1NIV56/6222/15 (improved)600Discharged2968/MESRDHTN, DM, CAD7NP, 4 L/min22/1023/18600Discharged3036/FAKI 3HTN, CKD, PTB6FM, 6 L/min36/1719/8600Discharged3148/MESRDHTN, CAD4NRBM 8 L/min96/4037/25 (improved)600Died3258/MAKI 2HTN, DM, KTR4FM, 4 L/min49/2225/24600Discharged3350/MAKI 3HTN, DM, PTB4FM, 6 L/min27/2519/18600Died3458/MAKI 3CKD, nephrolithiasis18NIV12/1218/10500Died3571/FAKI 3HTN, DM, CKD7FM, 4 L/min17/1119/11600Discharged3660/MESRDHTN, DM10FM, 8 L/min52/2535/21 (improved)600Died3780/MESRDHTN, CKD, nephrolithiasis15NRBM, 15 L/min55/1026/24 (improved)600Discharged3870/MAKI 3HTN, DM, CKD5NP, 2 L/min25/1925/24600Admitted (4)3952/MAKI 3HTN, DM, CKD14NP, 2 L/min31/1819/20600Discharged4073/MESRDHTN, DM15FM, 6 L/min42/2934/23600Admitted (4)4130/FAKI 3SLE, CKD4FM, 6 L/min41/1639/18600Died4225/MAKI 1HTN, DM, KTR3NP, 4 L/min57/50Day 5: 41/108 (persistent grade 1 ALT elevation), day 6: 37/140, day 9: 28/99 (improving)600Admitted (4-3)4382/MESRDHTN1FM, 4 L/min25/1024/14600Admitted (4)4457/FAKI 3RHD3NRBM, 15 L/min32/54(Ongoing) day 3: 24/28 (improving)400Admitted (5)4564/MAKI 3HTN, DM, CKD5NIV23/1747/21600Admitted (6)4636/FESRDHTN, CKD, PTB10FM, 4 L/min12/14(Ongoing) day 2: 11/14200Admitted (4)CAD, coronary artery disease; CKD, chronic kidney disease; DM, diabetes mellitus; ESRD, end-stage renal disease; F, female; FM, face mask; HFNC, high flow nasal cannula; HTN, hypertension; KDIGO, Kidney Disease: Improving Global Outcomes; KTR, kidney transplant recipient; M, male; NIV, noninvasive ventilation; NP, nasal prongs; NRBM, non-rebreathing mask; PTB, pulmonary tuberculosis; RHD, rheumatic heart disease; SLE, systemic lupus erythematosus; WHO, World Health Organization.Reference upper limit of normal for men and women: ALT ≤ 40 IU/L, AST ≤ 40 IU/L.a Further trend of AST/ALT not available. Open table in a new tab CAD, coronary artery disease; CKD, chronic kidney disease; DM, diabetes mellitus; ESRD, end-stage renal disease; F, female; FM, face mask; HFNC, high flow nasal cannula; HTN, hypertension; KDIGO, Kidney Disease: Improving Global Outcomes; KTR, kidney transplant recipient; M, male; NIV, noninvasive ventilation; NP, nasal prongs; NRBM, non-rebreathing mask; PTB, pulmonary tuberculosis; RHD, rheumatic heart disease; SLE, systemic lupus erythematosus; WHO, World Health Organization. Reference upper limit of normal for men and women: ALT ≤ 40 IU/L, AST ≤ 40 IU/L. Remdesivir (COVIFOR, Hetero Labs Limited [Hyderabad, India], under license from Gilead Sciences, Inc [Foster City, CA]) was administered as a total dose of 600 mg (200 mg on day 1, followed by 100 mg/day), which was extended in 2 patients to 1200 mg because satisfactory clinical improvement was not observed. The median number of days from hospital admission to starting remdesivir was 5 days (range 1–26 days). The median duration of follow-up was 15.5 days (range 6–81 days). Thirty-six (78.2%) patients were on dialysis (ESRD [n = 16] and AKI [n = 20]) at the time of initiation of therapy. Therapy could not be completed in 6 patients who died. Remdesivir was discontinued early because of clinical improvement in 2 patients, and therapy is ongoing in 2 patients. Most patients tolerated the infusion well except for patient 43 who had an infusion reaction with hypertension, breathlessness, and a drop in oxygen saturation, and the patient responded immediately to steroids and antihistamine treatment. Transient behavioral changes were noted in 5 cases and acute gout was observed in 1 patient while they were undergoing therapy (World Health Organization–Uppsala Monitoring Center causality category: possible) (Supplementary Methods). Baseline liver function test abnormalities (elevated aspartate aminotransferase [AST]/alanine aminotransferase [ALT] levels) were noted in 14 (30.4%) cases before starting remdesivir—grade 1 elevation in 13 patients (AST in 4, ALT in 1, and both AST and ALT in 8) and grade 2 elevation in 1 patient, which improved by the end of therapy in 12 cases. Liver function remained stable in 28 (60.9%) cases. Three (6.5%) patients were found to have newly occurring grade 1 elevations of AST/ALT during therapy. No patient had a severe rise in AST/ALT >5 times the upper limit of normal, therefore therapy was not required to be discontinued for this reason in any of the patients. No renal function abnormalities attributable to drug were observed (Table 2). Fourteen (30.4%) patients died, 24 (52.2%) patients were discharged from the hospital after recovery, and 8 (17.3%) cases are still admitted, of which 2 are still undergoing treatment.Table 2Renal function during remdesivir therapy in patients with AKICaseSerum creatinine at admission, mg/dlKDIGO AKI stageSerum creatinine before initiation of remdesivir, mg/dlPeak serum creatinine on remdesivir therapy, mg/dlSerum creatinine at completion/within 48 hrs of therapy, mg/dl36.63On dialysisOn dialysisDeathaSerum creatinine values not available.415.63On dialysisOn dialysisOn dialysis67.73On dialysisOn dialysisOn dialysisbPatient 6 achieved dialysis independence 5 days after the completion of therapy (creatinine at discharge 2.5 mg/dl). Patient 35 received 2 sessions of dialysis before remdesivir therapy, after which creatinine showed a dropping trend.78.03On dialysisOn dialysisDeathaSerum creatinine values not available.87.93On dialysisDeathaSerum creatinine values not available.DeathaSerum creatinine values not available.106.13On dialysisDeathaSerum creatinine values not available.DeathaSerum creatinine values not available.113.534.53.72127.332.92.72.5145.5343.73.2158.23On dialysisOn dialysiscPatient 15 received 1 session of hemodialysis followed by peritoneal dialysis for 28 hrs. All other patients requiring dialysis were undergoing hemodialysis.DeathaSerum creatinine values not available.165.735.95.54182.122.32.11.7194.7236.042.2207.03On dialysisOn dialysisDeathaSerum creatinine values not available.222.3212.22.32.12311.83On dialysisOn dialysisDeathaSerum creatinine values not available.246.73On dialysisOn dialysisOn dialysis261.611.61.61.4279.03On dialysisOn dialysisOn dialysis308.73On dialysisOn dialysisOn dialysis322.022.01.71.4336.03On dialysisOn dialysisOn dialysis349.83On dialysisOn dialysisOn dialysis354.136.8bPatient 6 achieved dialysis independence 5 days after the completion of therapy (creatinine at discharge 2.5 mg/dl). Patient 35 received 2 sessions of dialysis before remdesivir therapy, after which creatinine showed a dropping trend.6.66.13811.03On dialysisOn dialysisOn dialysis399.83On dialysisOn dialysisOn dialysis417.33On dialysisOn dialysisOn dialysis421.411.791.91.5444.73On dialysisOn dialysisOn dialysis4511.53On dialysisOn dialysisOn dialysisAKI, acute kidney injury; KDIGO, Kidney Disease: Improving Global Outcomes.All patients with end-stage renal disease were receiving hemodialysis or slow, low efficacy dialysis as a modality of renal replacement.a Serum creatinine values not available.b Patient 6 achieved dialysis independence 5 days after the completion of therapy (creatinine at discharge 2.5 mg/dl). Patient 35 received 2 sessions of dialysis before remdesivir therapy, after which creatinine showed a dropping trend.c Patient 15 received 1 session of hemodialysis followed by peritoneal dialysis for 28 hrs. All other patients requiring dialysis were undergoing hemodialysis. Open table in a new tab AKI, acute kidney injury; KDIGO, Kidney Disease: Improving Global Outcomes. All patients with end-stage renal disease were receiving hemodialysis or slow, low efficacy dialysis as a modality of renal replacement. We observed no clinically significant ALT elevations and no patients needed early discontinuation of therapy because of side effects. Twenty-four treated patients were discharged from the hospital. No significant abnormalities of renal function attributable to the drug were noted in any of the patients. Apart from dexamethasone,3RECOVERY Collaborative Group, Horby P, Lim WS, et al. Dexamethasone in hospitalized patients with Covid-19 – preliminary report [e-pub ahead of print]. N Engl J Med. https://doi.org/10.1056/NEJMoa2021436. Accessed November 1, 2020.Google Scholar remdesivir is the only other pharmaceutical agent approved for use in COVID-19. Trials evaluating this agent have excluded patients with impaired kidney function, so there are no data on its efficacy and safety in renal failure. The national clinical management protocol4Director General of Health Services, Ministry of Health and Family Welfare, Government of IndiaClinical management protocol: COVID-19 (version-5). New Delhi: EMR Division.https://www.mohfw.gov.in/pdf/UpdatedClinicalManagementProtocolforCOVID19dated03072020.pdfDate accessed: August 8, 2020Google Scholar states that the use of remdesivir is contraindicated in patients with eGFR <30 ml/min/1.73 m2 or when there is a need for hemodialysis. A policy of withholding its use in patients with kidney diseases because of lack of safety data can deprive these patients of one of the only available therapeutic options. Although remdesivir has not been shown to reduce mortality, its use decreased the time to recovery in patients with moderate and severe COVID-19. It has been suggested that remdesivir can be used with close monitoring in patients with renal impairment.5Adamsick M.L. Gandhi R.G. Bidell M.R. et al.Remdesivir in patients with acute or chronic kidney disease and COVID-19.J Am Soc Nephrol. 2020; 31: 1384-1386Crossref PubMed Scopus (132) Google Scholar Unmodified alpha- and beta-cyclodextrins are typically reabsorbed and concentrated in renal tubules and interact with cellular structures affecting cell integrity. SBECD was designed to address this problem; it remains in an ionized state after glomerular filtration and does not undergo significant tubular reabsorption. Although SBECD accumulates in patients with decreased eGFR, elevation in the serum creatinine did not correlate with SBECD levels.6Luke D.R. Tomaszewski K. Damale B. Schlamm H.T. Review of the basic and clinical pharmacology of sulfobutylether-beta-cyclodextrin (SBECD).J Pharm Sci. 2020; 99: 3291-3301Abstract Full Text Full Text PDF Scopus (181) Google Scholar Moreover, SBECD carrier is effectively removed by dialysis; a 4-hour session removes almost half of the accumulated SBECD.7Luke D.R. Wood N.D. Tomaszewski K.E. Damle B. Pharmacokinetics of sulfobutylether-β-cyclodextrin (SBECD) in subjects on hemodialysis.Nephrol Dial Transplant. 2012; 27: 1207-1212Crossref PubMed Scopus (46) Google Scholar This is the first report of the use of remdesivir in patients with severely reduced kidney function, and our findings suggest that it is tolerated well. Mild derangement in the liver function tests at baseline improved post-treatment. Although it is not possible to attribute such improvement to drug use, it suggests that mild elevations in transaminases should not be considered as a contraindication. Our study has several limitations. Most of our patients were on hemodialysis, so we cannot comment on its safety in patients with severe renal impairment but not yet on dialysis. We did not measure serum concentration of the SBECD, so the extent of its accumulation in our patients is not known. However, accumulation of SBECD does not correlate with rise in creatinine. We used the aqueous formulation of remdesivir which has double (6 g vs. 3 g) the concentration of SBECD than powdered form, which can be preferentially used in patients with renal impairment. Although our patients tolerated the drug well, the safety and efficacy of remdesivir cannot be determined without control subjects. In conclusion, remdesivir was well tolerated in patients with AKI and CKD including those on hemodialysis. Larger, well-controlled studies evaluating its safety and efficacy in patients with kidney diseases are needed. All the authors declared no competing interests. 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