Remdesivir Administration in COVID-19 Patients With Renal Impairment: A Systematic Review : American Journal of Therapeutics

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Systematic Review and Clinical Guidelines

Remdesivir Administration in COVID-19 Patients With Renal Impairment: A Systematic Review

Davoudi-Monfared, Effat PharmD1; Ahmadi, Arezoo MD2; Karimpour-Razkenari, Elahe PharmD1; Shahrami, Bita PharmD1; Najmeddin, Farhad PharmD1; Mojtahedzadeh, Mojtaba PharmD1,*

Author Information
doi: 10.1097/MJT.0000000000001543

Abstract

INTRODUCTION

Severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2), the late 2019 Chinese epidemics, was first identified in Wuhan and then burst into the current catastrophic pandemic.1 The illness was named Coronavirus disease 2019 (COVID-19), which has led to the death of more than half a million worldwide up to now.2 Although attempts to find an effective treatment initiated from the early outburst of the pandemic, few approaches were found to work. Remdesivir was the first antiviral that received the conditional approval to be taken both for children ≥12 years and adults who need hospitalization for COVID-19.3

Remdesivir (RDV, GS-5734)—a novel nucleotide analog—has a broad-spectrum antiviral activity and inhibits RNA-dependent RNA polymerase. RDV first proposed antiviral activity against SARS and Middle East Respiratory Syndromes, and the previous 2 coronaviruses.4,5 Several clinical trials reveal a shortening time to clinical improvements of COVID-19 patients who received RDV.6,7 The earlier studies on RDV showed no signs of a mortality benefit; however, further clear-cut studies and additional data collection of the disease cast light on the positive correlation between RDV and survival rates.8,9

The suggested dose of RDV is 200 mg intravenously on day 1, followed by 100 mg daily for additionally 4 days. The duration of treatment may be extended up to 10 days in case either there is no clinical improvement or in patients on mechanical ventilation or extracorporeal membrane oxygenation.10 The main RDV trials excluded COVID-19 patients with severe renal impairment, that is, estimated glomerular filtration rate (eGFR) of <30 mL/min per 1.72 m2.11 However, the pharmacokinetics (PK) of RDV has not been evaluated in the population of these patients.

RDV nephrotoxicity was proposed due to mitochondrial toxicity and inhibition of mammalian RNA and DNA polymerase by other antiviral agents such as tenofovir. However, this effect is observed after prolonged exposure.12 In addition, the excipient sulfobutyl ether-beta-cyclodextrin sodium salt (SBECD) is used in the formulation of RDV, which is renally cleared and potentially accumulated in the setting of decreased renal function. Therefore, the manufacturer's labeling does not recommend the administration of RDV in patients with an eGFR of less than 30 mL/min. Patients with renal impairment are prone to severe types of COVID-19. Besides, COVID-19 can cause acute kidney injury (AKI), tubulopathy, and glomerulopathy, and the early presentation of the disease can be in the form of renal involvement.13 Hence, if RDV accepts eligibility according to international guidelines, these patients may benefit from RDV. Considering recent data about the use of RDV in patients with renal impairment, the present study aims at reviewing the current evidence on the prescription of RDV in COVID-19 patients with different stages of renal impairment, including AKI, chronic kidney disease (CKD), and end-stage renal disease (ESRD), requiring renal replacement therapy (RRT) and tries to reach a reasonable conclusion for the safe administration of this agent in the setting of kidney impairment.

METHODS

This systematic review was performed following the 2020 guidelines for Preferred Reporting Items for Systematic Review and Meta-Analysis.

Eligibility criteria

All types of original studies, such as retrospective, prospective, cohort, randomized control trial, case–control, cross-sectional, crossover, case series, and case reports, were appraised in this review if (1) they were performed in adults (≥18 year old), (2) RDV was used to treat COVID-19 patients with different stages of kidney injury, including CKD with eGFR of <30 mL/min per 1.72 m2, AKI, ESRD, hemodialysis (HD), other types of RRT such as peritoneal dialysis (PD) and continuous renal replacement therapy (CRRT), and kidney transplant (if the study includes eGFR of <30 mL/min per 1.72 m2), and (3) English language was used as the medium. Simultaneously, the review articles, nonhuman studies, irrelevant articles, abstracts without full text (like the one for scientific congress), and duplications were excluded.

Search strategy and selection of studies

All published articles in databases (MEDLINE, ScienceDirect, Cochrane Library, PubMed), to the date of March 2, 2022, were thoroughly explored using the following keywords: “(COVID) OR (SARS-COV-2) AND (CKD) OR (AKI) OR (Renal impairment) OR (Kidney injury) OR (Hemodialysis) OR (Kidney transplant) OR (Renal replacement therapy) AND (Remdesivir) OR (RDV).” Two review authors (E.K.R. and E.D.M.) separately screened the titles and abstracts of the articles and screened the full texts individually to identify qualified studies. Any disputes were resolved by discussion to reach a logic consensus.

Data extraction

The review authors individually extracted necessary data from the included studies based on structured and standardized forms. The data consisted of the first authors' names and publication time, study design, sample size, number of patients with different kidney impairments, and main findings (interesting results, adverse effects of RDV in this subpopulation, and mortality rate if reported).

Quality assessment

Quality and risk of bias for each study were assessed by Joanna Briggs Institute critical appraisal checklist for cross-sectional, cohort, case report, and case series studies. Each type of study consists of specific questions, and 2 authors (E.K.R. and E.D.M.) completed the checklist for each article. If there were any disagreements, they were supposed to discuss and reach compliance.

Statistical analysis

Because the types of studies were different, it was not possible to compare their information statistically, and the meta-analysis was not possible in these studies. Hence, the results are presented in the format of a systematic review.

RESULTS

Study selection

Searching in mentioned databases and manual search resulted in 427 articles. Twenty-six articles were selected after a rapid review of both titles and abstracts. Finally, 22 articles were found to be eligible to be included in this review. Eight cohort studies, 8 observational investigations, 3 case reports, and 3 case series were among the selected ones. Figure 1 clearly illustrates the flowchart of screening and inclusion of the articles.

F1
FIGURE 1.:
Flowchart of screening and inclusion of eligible studies.

Quality and bias assessment

The quality and bias assessment of all eligible studies, including cohort, observational, case series, and case reports were assessed by Joanna Briggs Institute critical appraisal tool assist. Results are brought in Supplemental Digital Content 1 (see Tables S1–S4, https://links.lww.com/AJT/A117).

Summary of studies

Table 1 summarizes findings of articles. The number of patients with ESRD and HD, CKD, AKI, and other subtypes of renal impairment is brought in the table. Data analysis of these studies showed that patients with renal impairment who received RDV include 327 patients with eGFR below 30 mL/min per 1.72 m2, 238 patients with ESRD on RRT, 177 patients with AKI, and 117 patients with kidney transplant. These categories may overlap in some cases because some studies have categorized patients as eGFR below 30 mL/min per 1.72 m2 and did not clarify how many patients with CKD or HD or AKI are in this range. As it is obvious in the table, much research has focused on rates of RDV side effects in patients with kidney impairment.

Table 1. - Summary of included studies.
No. Authors Time of publication Study design Sample size No. of included patients with renal impairment Main findings Ref
1 Thakare et al October 2020 Retrospective observational 46 ESRD with RRT: 16
AKI: 30
No renal function abnormalities attributable to drug
Mortality rate: 30.4%
Survival rate: 52.2%
Continuation of admission: 17.3%
( 14 )
2 Sorgel et al November 2020 Case report 1 ESRD with RRT: 1 PK study of RDV and 2 metabolites was performed
Exposure for RDV and GS-441524 metabolite after the first dose was about 3-fold and 6-fold higher as compared with healthy volunteers
HD reduced GS-441524 plasma concentrations by approximately 50%
Overall, there were no signs of drug-related toxicity, including hepatic and renal
( 15 )
3 Aiswarya et al. December 2020 Prospective observational 48 ESRD with RRT: 48 Patients received 2–6 doses of RDV between 5 and 11 days
Mortality rate: 20.3%
There was a significant decrease in the serum level of CRP after RDV therapy (P < 0.001), but no change in LDH and ferritin level
18.7% had elevated AST (>45 IU/L) and 12.5% had elevated ALT levels (>55 IU/L), with a median ALT level of 66 IU/L
( 16 )
4 Peyko et al December 2020 Case report 1 AKI (on HD): 1 RDV was started and HD was performed next day until discharge from hospital
No adverse event was reported due to RDV
( 17 )
5 Ackley et al January 2021 Multicenter matched cohort 347 eGFR < 30: 40 Age, receiving vasopressor, and mechanical ventilation on the day of RDV initiation were significantly different between patients with an eCrCl of <30 versus those with an eCrCl of ≥30
There was no significant difference in the frequency of EOT AKI and discontinuation due to abnormal LFTs
Patients with an eCrCl of <30 had a higher 30-day mortality rate
Of the 2 patients who developed EOT AKI on RDV with an eCrCl of <30, no cases were attributable to RDV administration
( 18 )
6 Van Laar et al. March 2021 Retrospective observational 103 30 < eGFR < 50: 15
eGFR < 30: 6
10 (10.5%) of all patients (including 2 of the patients with eGFR below 50) had a decrease in eGFR of >10, and the maximum decrease in eGFR was 21
Also, 25% and 35% had increased in ALT and AST, respectively
2 patients ended up treatment with RDV soon, and none was related to RDV toxicity
( 19 )
7 Davis et al March 2021 Case series 3 ESRD with RRT: 3 RDV half-life in 2 of the patients was 2 h twice as healthy volunteers
A decline in RDV concentration in each patient was accompanied by an increase in GS-441524 concentration (conversion from prodrug into metabolite)
The highest measured GS-441524 concentration (1470 ng/mL in patient 3) was approximately 10-fold higher than day 5 Cmax in healthy volunteers, that is, 142 ng/mL
( 20 )
8 Estiverne et al March 2021 Case series 18 Stable CKD with eGFR < 30: 8
ESRD with RRT: 2
AKI (not on RRT): 5
AKI (on RRT): 3
11 patients were ICU admitted and 9 were mechanically ventilated
2 patients developed ALT above 5 ULN
( 21 )
9 Meshram et al April 2021 Retrospective cohort 57 Kidney transplant: 57
eGFR < 30: 21
AKI: 38
The median SrCr at baseline and at 28-day follow-up was 1.59 and 1.58, respectively
The median admission serum creatinine was 2.13
1 patient lost the graft with a baseline creatinine of 5.2
Need for dialysis after treatment: 2%
Mortality rate: 14%
Complete recovery: 84%
( 22 )
10 Selvaraj et al May 2021 Retrospective observational 28 ESRD with RRT: 28 (14 RDV and 14 control) There was no difference in mortality rate and O2 requirement between the RDV group and the control
Mortality rate: 35.7%
( 23 )
11 Buxeda et al. July 2021 Multicenter cohort 51 Kidney transplant: 51
eGFR < 30: 2
The mortality rate was 18.9% and markedly higher if aged older than 65 years (45% vs. 3.2% in younger patients)
No patients required RDV. AKI developed in 14 patients and 8 of them presented the peak SCr before the initiation of remdesivir. Renal dysfunction could not be attributable to RDV. Totally, adverse events could not be related to drug itself (hepatotoxicity or other reactions)
(24)
12 Shakir et al July 2021 Prospective cohort 34 AKI: 16
CKD: 14
Kidney transplant: 4
The patient with baseline kidney disease and development of kidney impairment during RDV therapy were included. Then survivors and nonsurvivors were compared
More than 50% of patients were categorized as severe ARDS
The mode of oxygenation and inflammatory markers (CRP and LDH) was significantly different between survivors and nonsurvivors
Mortality rate: 52.9%
Two patients had hepatic dysfunction at the baseline (both died), and 5 developed hepatic dysfunction after RDV therapy (3 of them died)
( 25 )
13 Shah et al September 2021 Cohort 1000 AKI: 74 (38 in lyophilized powder of RDV group and 36 in solution of RDV group)
eGFR < 30: 119 (53 in lyophilized powder of RDV group and 66 in solution of RDV group)
Kidney transplant: 7
The goal was evaluation the risk of adverse effects between patients receiving RDV lyophilized powder and injectable solution that was not different
Mortality rate: 30.2% (lyophilized powder group), 42.4% (solution group)
Mechanical ventilation and receiving vasopressor (and not eGFR below 30) were only factors related to the incidence of AKI
( 26 )
14 Oktavianto et al. October 2021 Case report 1 ESRD with RRT: 1 The main aim of the study was not to use RDV in renal impairment
The patient was on regular HD and after being infected, received RDV while being on CRRT, and CRRT was continued while outpatient
( 27 )
15 Schieber et al December 2021 Retrospective cohort 151 eGFR < 30: 21 (11 on HD) Adverse event rates in the patient with eGFR of <30 mL/min were like all other patients
In all patients, the incidence of AKI starting with the initiation of RDV was 6%, and LFT adverse events occurred in 5% of patients
In the patient with an eGFR of < 30 mL/min, AKI occurred in none and the hepatic adverse event occurs in only one case
( 28 )
16 Pettit et al December 2021 Retrospective observational 135 eGFR < 30: 15 (including 13 AKI on CKD, 1 AKI, 1 CKD)
RRT: 5
Patients with severe renal impairment were significantly older (70 vs. 54 years, P = 0.0001)
Most patients in both groups were Black/African American
Out of 15 patients with eGFR < 30, 3 required HD after the end of RDV therapy
The median baseline SrCr was 2.6 in the SRI group (of those not receiving RRT) compared with 0.9 in patients without SRI
The median SrCr at the end of RDV therapy was 1.8 in patients with severe renal impairment (not receiving RRT) compared with 0.8 among patients without
The incidence of possible adverse effects was 30% among those with severe renal impairment versus 11% without (P = 0.06).
LFT and SCr elevations were not attributed to RDV in either group
( 29 )
17 Wang et al December 2021 Retrospective observational 71 CKD with eGFR < 30: 53
HD: 14
Kidney transplant with eGFR < 30: 4
eGFR improved from baseline to the end of treatment, and 48 h after the treatment (30.3% and 30.6% respectively, P < 0.0001)
Elevation of AST was observed at the end of RDV treatment (2.5%, P = 0.727). But AST reduction was seen 48 h after the end of treatment (15.8%, P = 0.021)
AKI during treatment: 35% (14% of total death)
Mortality rate: 33.8%
Other nephrotoxic drugs and attributable conditions for AKI were reported in patients with AKI
( 30 )
18 Banerjee et al December 2021 Retrospective observational 58 (4 received RDV) ESRD with RRT: 4 No patients experienced infusion reaction or elevation in hepatic transaminase ( 31 )
19 Butt et al January 2022 Prospective cohort 83 ESRD with RRT: 83 All patients were on HD and enrolled in each of 2 groups: receiving RDV before and after 48 h of admission
The mortality rate in whom received RDV before and after 48 h of admission was 7.8% and 12.5%, respectively
Total mortality rate: 8.34%
Three patients had increased ALT, whereas 2 patients experienced minor reactions
( 32 )
20 Selvaraj et al January 2022 Retrospective multicenter observational 45 ESRD with RRT: 45 (20 RDV and 25 control) RDV decreased the risk of ventilation and mortality in the subset of patients without DM and with low D-dimers
None of the patients stopped treatment, due to hepatic side effects
( 33 )
21 Seethapathy et al February 2022 Retrospective cohort 62 eGFR < 30: 62 (31 received RDV within 72 h of admission) There were no significant differences in adverse events except for an increased incidence of hyperglycemia in the RDV group (81% of patients in the RDV arm received dexamethasone in comparison to 55% in the control arm)
RDV was discontinued early in 4 patients (14%): 2 due to elevated transaminase levels and 2 due to concerns regarding low eGFR (none of the 2 patients experiencing above 50% increase in SrCr)
There was no increased risk of cardiac arrhythmia, cardiac arrest, altered mental status, clinically significant anemia, or liver function test abnormalities
( 34 )
22 Al Bishawi et al In press Case series 5 eGFR < 30: 5
Kidney transplant: 1
Only one case required ICU admission
Duration of hospital stay was between 7 and 21 days
All were either improved or cured and discharged successfully
( 35 )
AE, adverse effect; ALT, alanine aminotransferase; ARDS, acute respiratory distress syndrome; AST, aspartate aminotransferase; CRP, C-reactive protein; eGFR, estimated glomerular filtration rate (the unit is mL/min per 1.72 m2 throughout the table); EOT, end of treatment; ICU, intensive care unit; LDH, lactate dehydrogenase; LFT, liver function test; O2, oxygen; Ref, reference; SrCr, serum creatinine (the unit is mg/dL throughout the table); SRI, severe renal impairment; ULN, upper limit of normal.

Mortality or survival rate of the patients are reported in the table. The concern is mostly focused on safety of the drug, due to the risk of accumulation of the drug and its metabolites in renal impairment. The main adverse effects that are presented in the table are renal and hepatic. Other adverse effects were not addressed, even though they were reported in the article. Interfering factors like mechanical ventilation, vasopressor administration, and pharmacokinetic studies are mentioned in the main findings in the table, if they are reported in the articles.

DISCUSSION

COVID-19 can lead to kidney failure through multiple mechanisms, such as direct virulence of SARS-CoV-2, especially in presence of angiotensin-converting enzyme-2 (ACE2) receptors, medullary hypoxia, cytokine damage, hypo and hypervolemia, and other secondary infections.36 In addition, the early trials of RDV in COVID-19 excluded patients with kidney and liver disease, so no data are extracted from those clinical trials, and that is why the adjustment of RDV dose in both acute and chronic renal impairment remains a dilemma yet. A total of 22 studies were included in the present systematic review. The ranges of mortality rates were reported to be 7.3%–50%, and the highest rate was found in a study in which about half of participants were categorized with severe acute respiratory distress syndrome. An increase in the incidence of adverse effects, such as hepatic and kidney injury, was not reported, whereas a decrease in inflammatory mediators and improvement in kidney function (decrease in serum creatinine after RDV therapy) was presented in the findings of one observational study included in this review. However, this study had no comparison group.30

Evidence about the use of RDV in different types of renal impairment

Almost all clinical trials of RDV administration in COVID-19 have excluded patients with eGFR below 30 mL/min per 1.72 m2. The reason behind this was due to both the lack of safety study and accumulation of parent drug, its metabolite, and their probable nephrotoxicity. It is noteworthy to state that mitochondrial injury, as the main mechanism of tubular injury by RDV as a nucleotide/nucleoside analogue, inhibiting nonmammalian DNA and RNA polymerase, rarely happens with a 5- or 10-day exposure.37 In addition, clinical trials did not report any increase in the rate of kidney injury in the RDV arm.11

CKD

A total of 327 patients with eGFR less than 30 mL/min per 1.72 m2 were included in this review, and most of them were CKD with stable serum creatinine. None of the investigations reported any increased risk of adverse effects. Although the risk of AKI is assumed to co-occur with RDV administration, and AKI was reported to be up to 35% in the study of Wang et al,30 it was not clearly attributed to RDV alone. However, this study reported improvement in the mean eGFR at the end of treatment. The findings of a study by Meshram et al22 confirm this result too. In this study, the mean serum creatinine improved after the administration of RDV. Age was considered a critical risk factor for this subpopulation. Moreover, in the study of Pettit et al,29 patients with renal impairment were significantly older in comparison with those with eGFR above 30 mL/min per 1.72 m2. This study revealed higher rates of adverse effects. Another study by Buxeda et al24 showed higher mortality rates in patients older than 65 years. Age was significantly different between patients with eGFR under and above 30 mL/min per 1.72 m2 in the study of Ackley et al18 too. Although age is a confounding factor in comparison of patients with and without CKD, the adverse effect was not related to RDV even in older patients with renal impairment.

ESRD with RRT

In patients undergoing HD, the concern is less serious because RDV, its metabolites, and SBECD are dialyzable.38,39 One case report showed that after the first dose of RDV, the level of the parent drug and GS-441524 metabolite grew to about 3-fold and 6-fold higher compared with healthy subjects, but this level could decline to 50% after HD.15 The findings stand in favor of RDV administration in patients undergoing RRT, albeit more PK and clinical trials are still required in this subpopulation of patients.

AKI

The study of Shah et al26 was the largest study with the inclusion of 74 patients with AKI to receive either lyophilized powder or solution of RDV. Investigation of side effects, including renal and hepatic injury, showed no difference between patients with or without renal impairment. Another study by Aiswarya et al16 included 38 patients with AKI who were treated with RDV, and the findings reported an improvement in serum creatinine. AKI can be the consequence of some clinical conditions like tubulopathy and glomerulopathy of COVID-19, dehydration, and renal hypoperfusion.40 However, the use of antiviral in eligible patients indicates helpful. However, data on the modification of the drug's volume of distribution, other PK parameters, and exact serum concentration of drug and metabolites in AKI are limited. So, more PK studies are yet to be done to confirm safe RDV administration in patients with AKI.

Kidney transplant

Patients with a history of kidney transplant were included in most of the studies in the present review, but 2 studies had the largest sample size.22,24 In both studies, side effects did not lead to discontinuation of the RDV, and improvement in serum creatinine was observed following treatment. One study also reported RDV administration in 20 kidney transplant recipients, but it is not included in the present review due to the acceptable eGFR range according to clinical trials (above 30 mL/min per 1.72 m2) in all patients.41 Early hospitalization and severity assessment of COVID-19 were emphasized in this study. It seems that RDV therapy is helpful in kidney transplant patients with COVID-19. If the eGFR is below 30 mL/min per 1.72 m2, the consideration for CKD patients (as noted above) should be emphasized. Figure 2 summarizes the use of RDV in various types of renal impairment.

F2
FIGURE 2.:
Summary of use of RDV in various types of renal impairment. Color green indicates safe use. Color yellow shows that there is a lack of large well-designed studies, but toxicity is less concerning due to HD and removal of drug, and vehicle. Color orange shows that there is a lack of large well-designed studies, and the risk of accumulations of drug and metabolites remains.

Adverse effects of RDV in patients with renal impairment: increase or no change?

Evaluation of side effect risks in kidney impaired subpopulations was performed in several studies that are enrolled in this review. Hepatic injury (in the form of an increase in liver enzymes), nephrotoxicity, and gastrointestinal side effects are proposed as concerns about RDV use.12,42 In the present review, almost none reported significant differences in the incidence of side effects in patients with kidney disease in comparison with patients with normal renal function. It should be addressed that one big limitation of most of included studies was that they were retrospective and observational. Otherwise, as a part of rational safety assessment, only Thakare et al14 and Wang et al30 performed causality assessment for adverse effects and other studies did not, which is a weakness point for them.

In the study of Shah et al,26 which had the largest sample size of patients with renal impairment (119 patients), AKI occurred in 7.4% with no increase in drug nephrotoxicity or hepatotoxicity. A significantly higher rate of adverse effects was only observed in one research among patients with eGFR under 30 mL/min per 1.72 m2 (30%) compared with patients with eGFR above 30 mL/min per 1.72 m2 (11%). In this study, the mean age of patients with kidney damage and normal renal function stood at 70 and 54 years old, respectively; this may explain the higher incidence of adverse effects, and thus, the issue was not attributed to therapy with RDV.29 The research of Seethapathy et al34 reported a higher incidence of hyperglycemia in patients with eGFR below 30 mL/min/1.72 m2 who were treated with RDV during their first 72 hours of hospital admission. However, it may not be related to RDV and was probably due to the dexamethasone prescribed in 81% of patients in comparison with 55% of the control arm. RCTs and observational studies have reported elevation in liver transaminase in patients for whom RDV was prescribed.42 Although the half-life of RDV and its metabolite is increased in patients with kidney impairment, the concern about liver injury may increase. Although 9 studies reported hepatic enzyme elevation, none reported liver failure. However, this side effect could not be directly related to RDV therapy.

SBECD vehicle

SBECD is a highly soluble solid that is used for the solubilization of different medications, including RDV.43 An early hypothesis proposed that SBECD can be accumulated in renal epithelial cells in case of receiving intravenous voriconazole in patients with renal dysfunction, yet this is not confirmed in recent studies.44 In fact, SBECD is accumulated in patients with renal impairment and causes tubular vacuolation, but it does not reabsorb in renal epithelial cells and does not lead to renal injury.45 Each 100 mg of solution and lyophilized powder of RDV contain 6 and 3 g of SBECD, respectively. As it was proposed for voriconazole, the accumulation of SBECD has been associated with renal tubular vacuolation and nephrotoxicity in animal models, but the doses is 50- to 100-fold higher than what is administered during a course of 5 or 10 days of treatment with RDV.46,47 The maximal safety dose for SBECD is 250 mg/kg (ie, suggested by the EMA safety report). Considering the dialyzable identity of SBECD and the decrease in its half-life in patients who underwent HD, the concern would be much lower in HD patients for whom RDV is prescribed.38

The necessity of RDV in COVID-19 patients with renal impairment

Early clinical trials of RDV in COVID-19 showed no significant difference in terms of clinical recovery, need for low- or high-flow oxygen supplementation, or change of mortality rates. However, in these trials, RDV could decrease the probability of mechanical ventilation or ECMO.11 Another consideration in early investigations was the efficacy and superiority of either a 5-day or a 10-day RDV regimen. The 10-day regimen recorded no benefits regarding the clinical improvement of patients.48 As the knowledge about COVID-19 and different phases of the disease (viral and inflammatory phase) improved, new issues were proposed about the use of antivirals, especially RDV. In the first step of infection, SARS-CoV-2 infects the epithelial and endothelial cells in the host lung.49 ACE-2, as an important target for the virus, can be downregulated, resulting in a more severe lung injury.50 In this phase, the concentration of the virus in the lung is high. This step can progress to respiratory failure in susceptible individuals on day 8 or 9 of the disease, when the SARS-CoV-2 is detectable, though in low amounts, and severe hyperinflammation has entangled all immune systems and even major organs.51 The first phase is the opportunity window for most antivirals, such as RDV. The route of investigations of RDV was completed with more clear-cut clinical trials, so international guidelines recommend a 5-day RDV regimen for patients with mild-to-moderate COVID-19, who are at risk of progression to severe disease, especially within 7 days of onset of symptoms. Also, in patients with severe COVID-19 (with SpO2 ≤ 94% on room air), RDV is suggested over no antiviral therapy.10 A recent meta-analysis showed that RDV has mortality benefits in comparison with placebo at day 14 of treatment.52 The new investigations suggest a benefit of an early 3-day treatment using RDV in outpatients. This resulted in a statistically significantly lower risk of mortality and admission to the hospital (P = 0.008 and CI = 0.03–0.59). These findings highlight that RDV can have a mortality benefit if administered to eligible patients within the right time.

Patients with different forms of renal impairment are at high risk for developing severe disease and mortality of COVID-19.53 On the other hand, many studies on cadavers have shown centered around endothelial derangements, coagulation, inflammation, and micro- or macrovascular dysfunctions that are the result of organ–organ interaction.54 The SARS- CoV-2 is tightly related to the host ACE-2 receptor by the S1 protein. Binding the ACE-2 receptor and cellular transmembrane serine proteases (TMPRSS) is essential for the viruses to enter the cells and tissues which expresses the ACE-2 receptor and TMPRSS simultaneously.55 Heart, lung, kidney, and intestinal tract are exposed to those receptors and clinical manifestations, such as myalgia, respiratory failure, diarrhea, proteinuria, arrhythmia, and myocarditis, that may indicate cardiopulmonary and renal involvement in COVID-19.56,57 However, independent of its origin, acute respiratory distress syndrome patients have an increased risk for the development of AKI, which is a common extrapulmonary organ dysfunction seen following SARS-CoV-2.58 According to postmortem autopsy, the most common pathophysiologic pathways for kidney injury are tubular injury, collapsing glomerulopathy, and endothelial injury caused by thrombotic microangiopathy, among which, the last is related to damage-associated molecular pattern and pathogen-associated molecular pattern.13 The presence of the virus was not confirmed in early investigations, but next studies isolated viral RNA from the postmortem kidney tissue.54,59 On the other hand, patients with renal disease are prone to severe forms of COVID-19. Considering both populations, including patients with previous kidney disease and patients with COVID-19–induced tubulopathy and glomerulopathy, a notable number of patients who are at great risk of progression to severe form of COVID-19 are being deprived of the benefits of RDV therapy, particularly if they are in their early course of illness. That is why the clarification of the use of RDV in both populations should be addressed in future well-designed studies.

Bright and blind spots in PK of RDV

Despite the increasing knowledge on the place of RDV in the treatment of COVID-19, data about its PK are still insufficient. RDV is rapidly metabolized to C-adenosine nucleoside analogue GS-441524. It is distributed in tissues and blood cells, where it is activated to triphosphate analogue (GS-443902). One study on PK parameters in healthy subjects revealed a linear profile of RDV following either single- or multiple-dose administration. But the level of metabolite GS-441524 would increase by 1.9-fold following daily administration.60 The volume of distribution of RDV is approximately 85.5 L after multiple-dose of 150 mg daily for 1 to 2 weeks.60 Approximately 80% of RDV is metabolized by carboxylesterase and, to a lesser extent, by cathepsin A and CYP3A.61 The main metabolite is renally excreted to 74%, and the level of intact RDV in urine is very low, that is, 10%.62 Another report of PK parameters suggested a higher concentration of the metabolite in a patient with mild renal dysfunction and presence of metabolite in cerebrospinal fluid and bronchoalveolar lavage.63

The physiological consequences of organ–organ interactions following COVID-19 may have a pronounced effect on the kinetics of elimination of RDV and its metabolite. The augmented renal clearance (ARC) characterized by increased creatinine clearance and elimination of renally eliminated pharmaceutical products may develop in the settings of pathogen-associated molecular pattern, sepsis, trauma, and burns, and also, it may happen in patients with COVID-19.64 ARC is associated with suboptimal exposure to critical antimicrobial agents, including beta-lactams, vancomycin, and antivirals.55 It is not clear if RDV undergoes ARC or not.

The PK profile of RDV in renal impairment is scarce. One study included in this review showed that RDV half-life in 2 of the patients was 2 hours (twice as healthy volunteers). Also, the highest measured GS-441524 concentration was 1470 ng/mL, which was approximately 10-fold higher than day 5 Cmax in healthy volunteers.15 More investigations are required to clearly define PK parameters of RDV in patients with kidney disease and answer the questions about probable changes in PK parameters of the drug and metabolites in this subpopulation toward optimization of drug therapy and individualized treatment for RDV. Otherwise, although it seems that dose modification and decrease in dose is necessary, the extend is not clear, according to current information.

Study limitations

This review had some limitations that should be addressed. First, well-designed studies have not been performed on the use of RDV in renal impairment, and most of the included studies were observational, case reports, and case series. Unlike observational reports and according to large database of adverse effect report of RDV, occurrence of renal failure and hepatic dysfunction is still a concern with RDV, and future well-designed trials should be performed to determine the true safety of RDV in patients with renal failure.65,66 Second, PK studies are critical for the assessment of serum concentration and PK parameters of the drug in the subpopulation of patients with renal disease, but investigations in this field are limited. Third, the included studies consist of different severity of COVID-19 (from mild to severe), so the mortality and complications cannot be compared without considering this factor. Last is about ambiguities on the incidence of other side effects of RDV like cardiotoxicity in patients with renal impairment.67 Only, one included study tracked cardiovascular side effects and reported no increase. However, future research should emphasize side effects other than hepatic and renal injury, too.

CONCLUSION

The safety of RDV administration in COVID-19 patients with renal impairment and eGFR below 30 mL/min per 1.72 m2 is ambiguous. To the best of our knowledge, this is the first systematic review that collects the investigations about the use of RDV in the setting of CKD, AKI, ESRD, RRT, and kidney transplant patients. Most of the included studies were observational, case reports, and case series. However, the rate of adverse effects like renal and hepatic injury was not attributable to RDV in these patients. Moreover, RDV can be beneficial in COVID-19–induced AKI, so depriving these patients of RDV therapy may not help anymore. Performing well-designed studies and clinical trials can help, so that eligible patients in this subpopulation may benefit from RDV therapy.

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Keywords:

remdesivir; antiviral; coronavirus infection; kidney disease; SARS-CoV-2; dose adjustment

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