Whether Remdesivir Increases the Risk of Acute Kidney Injury (AKI) in Patients with COVID-19: A Systematic Review and Meta-Analysis

Background: Acute kidney injury (AKI) occurs among patients with COVID-19, it is also proved to be associated with in-hospital mortality. Remdesivir, an RNA polymerase inhibitor, has shown its antiviral activity in vitro and animal models. The adverse effect of Remdesivir especially AKI is the most common cause which lead to drug discontinuation. Whether Remdesivir increases the risk of AKI in patients with COVID-19 is not clear. We conducted a systematic review and meta-analysis to evaluate the incidence rate of AKI in hospitalized COVID-19 patients and whether Remdesivir increases the risk of AKI. Methods: A thorough search was carried out to nd relevant studies in PubMed, medRxiv, and Web of Science from 1 Jan 2020 till 1 June 2020. 15135 COVID-19 patients and 981 COVID-19 patients using Remdesivir were included in our meta-analysis. Results: The pooled estimated incidence of AKI in all hospitalized COVID-19 patients was 12.0% (95% CI:9.0%-15.0%). According to our subgroup study, the incidence of AKI was associated with the age, disease severity and race of patients. The incidence of AKI in hospitalized COVID-19 patients using Remdesivir was 6% (95% CI: 3%-13%) with a total of 5 studies. Comparing with COVID-19 patients without Remdesivir treatment, Remdesivir treatment do not increase the risk of AKI in COVID-19 patients showing OR 0.80(95%CI: 0.44-1.46, P>0.05). Conclusions: We found out that AKI was not rare in hospitalized COVID-19 patients. The incidence of AKI was associated with age, disease severity and race. Remdesivir treatment did not increase the risk of AKI in hospitalized COVID-19 patients. Our meta-analysis may provide an evidence for future study that AKI is associated with the natural cause of COVID-19, not the adverse event after the usage of Remdesivir. to more 10 million of infections thousand worldwide 1 Mortality of COVID-19 is among older patients with chronic diseases, including hypertension, diabetes, chronic kidney disease and cardiac disease Recent studies suggest that the development of acute kidney injury (AKI) during hospitalization in patients with COVID-19 is high and associated with a poor prognosis 3–5 . However, the exact rate of AKI associated with patients hospitalized with COVID-19 is not well understood. In this study, we performed a meta-analysis of the incidence rate of AKI in hospitalized patients with COVID-19. dysfunction, tubular cell injury, renal congestion, microvascular thrombi and endothelial dysfunction 38 . Pathology from autopsies of patients with COVID-19 with renal failure revealed that the kidneys had varying degrees of acute tubular necrosis, diffuse proximal tubule injury with the loss of brush border, non-isometric vacuolar degeneration, hemosiderin granules and pigmented casts 39,40 .We found out that incidence of AKI in all hospitalized COVID-19 patients was 12.0%. The diversity of patients included in our meta-analysis cause the heterogeneity. According to the subgroup analysis, the estimated AKI incidence of patients with averaged age more than 60 years old is higher than patients averaged age less than 60 years old (13% vs 8%). Many reports on COVID-19 have highlighted age-related differences in health outcomes, mortality of COVID-19 is particularly high among older patients 41,42 . Age is also an important risk factor for AKI 43 . The pooled estimated AKI incidences in the Asian subgroup was lower than Western subgroup (8% vs 28%). Black race is a risk factor for AKI 44 . In a large cohort study of hospitalization COVID-19 patients among black patients and white patients with COVID-19, 76.9% of the patients who were hospitalized with COVID-19 and 70.6% of those who died were black, whereas blacks comprise only 31% of the population 45 . The incidence of AKI in ICU patients with the COVID-19 was particularly high range from 8%-62% 15,18,23–25,28,29 . Critical ill patients

Background COVID-19, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to more than 10 million of infections and over 500 thousand deaths worldwide 1 . Mortality of COVID-19 is particularly high among older patients with chronic diseases, including hypertension, diabetes, obesity, chronic kidney disease and cardiac disease 2 . Recent studies suggest that the development of acute kidney injury (AKI) during hospitalization in patients with COVID-19 is high and associated with a poor prognosis [3][4][5] . However, the exact rate of AKI associated with patients hospitalized with COVID-19 is not well understood. In this study, we performed a meta-analysis of the incidence rate of AKI in hospitalized patients with COVID-19.
Given the current, ongoing pandemic of COVID-19, there is a need to identify safe and effective treatment options. Remdesivir (GS-5734), a prodrug of adenosine analogues, has been shown to have antiviral activity against several RNA viruses, including MERS-CoV and Ebola virus disease (EVD) 6,7 . Remdesivir effectively inhibit SARS-CoV-2 in vitro and in mice model 8,9 . In J.H. Beige et al's report, Remdesivir was superior to placebo in shortening the time to recovery in patients with COVID-19 and evidence of lower respiratory tract infection 10 . But according to the clinical experiment, the adverse effect of Remdesivir especially AKI is the most cause lead to drug discontinuation 11,12 . Whether Remdesivir increases the risk of AKI in patients with COVID-19 is still uncertain. Here, we further systematically review and metaanalysis the incidence rate of AKI in COVID-19 with the treatment of Remdesivir.

Search Strategy
A systematic literature search was performed using PubMed, Web of Science, and medRxiv from 1 Jan 2020 till 1 June 2020 to summarize the data of AKI with patients hospitalized with COVID-19 and using Remdesivir for treatment of COVID-19. Two authors independently carried out systematic literature searches employing the terms "acute kidney injury" OR "acute renal failure" AND "COVID-19" OR "SARS-COV-2" for the data of AKI incidence in patients hospitalized with COVID-19, at the same time, we also employing the terms "Remdesivir" AND "COVID-19" OR "SARS-COV-2" for the data of AKI incidence in COVID-19 patients with the treatment of Remdesivir. No language restrictions were applied.

Inclusion and Exclusion Criteria
Studies were included if they met the following criteria: 1) observational studies that reported the incidence rate of AKI in all hospitalized patients with COVID-19 and 2) observational studies or randomized, placebo-controlled trial (RCT) studies that reported the incidence rates of AKI in hospitalized patients with COVID-19 using Remdesivir.
Excluded studies that were 1) editorials, review articles or case reports, 2) studies with incomplete information about AKI, and 3) studies did not utilize the 2012 KDIGO criteria to de nite AKI.

Quality assessment
The methodological quality of retrospective cross-sectional studies was assessed independently by two reviewers (Chen and Xu) using the Agency for Healthcare Research and Quality (AHRQ) (http://www.ncbi.nlm.nih.gov/books/NBK35156). Studies achieving 8 or above were considered as high quality. At the same time, the randomized controlled trials (RCTs) in our study were analyzed using Cochrane collaboration's tool (http://handbook-5-1.cochrane.org/). It can be divided as group A, B and C. Studies which achieving "A" were considered as high quality.

Statistical Analysis
All the meta-analyses were performed using the R project (4.0.1). The proportion of AKI in COVID-19 patients (ratio variables) and odds ratio (OR) of the AKI incidence rate between different groups using Remdesivir or not (dichotomous variables) were used in our study. All results were reported with 95% con dence intervals (CIs). Statistical heterogeneity between studies was assessed using the chi-square test with signi cance set at P < 0.10 and heterogeneity was quanti ed using the I 2 statistic (I 2 < 50%). The random-effect model was used if there was heterogeneity between studies; otherwise, the xed-effects model was adopted. Sensitivity analysis was performed by one by one exclusion. Begger's test was performed for publication bias and the signi cance was considered if P < 0.05.

Literature Search and Study Characteristics
A total of 204 papers were collected according to our searching criteria. Of them, 159 publications were unrelated with AKI and therefore excluded from the study. 45 papers received full-article review, where 22 were excluded according to the exclusion criteria. The ow diagram of the selection process is shown in Fig. 1. Finally, 18 studies including 15135 all hospitalized COVID-19 patients met the prede ned inclusion criteria and were used for the incidence of AKI in all hospitalized COVID-19 patients. At the same time, 5 studies including 981 patients were used for the incidence of AKI in COVID-19 patients using Remdesivir for the treatment of COVID-19. Only two RCTs were chosen to compare the incidence of AKI between COVID-19 patients using Remdesivir or not. These two RCTs were of high quality.
Tables 1 and 2 showed the characteristics of the studies in this systemic review. All studies in our meta-analysis showing the incidence of AKI were retrospective cross-sectional studies and most of them with high quality (13/18). And the RCTs included in our study were also with high quality.

Remdesivir treatment does not increase the risk of AKI in patients with COVID-19
Until now, only 2 RCT were included in our study (Fig. 4)

Sensitivity analysis and publication bias
In sensitivity analysis, one by one exclusion found similar results as our study. Begger's test was performed for the evaluation of publication bias, and no signi cant difference (P > 0.05) was detected in the analysis of incidence of AKI in all hospitalized COVID-19 patients. Less than 10 of study number is not enough for the publication bias calculation in the analysis of incidence of AKI in hospitalized COVID-19 patients using Remdesivir for treatment.

Discussion
In this meta-analysis, results from 18 retrospective cross-sectional studies including 15135 patients hospitalized with COVID-19 from January 1, 2020 to June 1, 2020 demonstrated that AKI was not rare in COVID-19. The incidence of AKI is associated with the age, disease severity and race of patients in our subgroup study. And we also proved that using Remdesivir for treatment did not increase the risk of AKI.
COVID-19 infection is primarily a respiratory disease, but other organs including the kidneys are often involved. Renal abnormalities, such as proteinuria, hematuria, and AKI occurred in patients with COVID-19 34 . AKI is characterized by a rapid increase in serum creatinine, decrease in urine output, or both 35 . The currently widespread AKI de nition was developed by the Kidney Disease Improving Global Outcomes (KDIGO) group in 2012 36 . The most common causes of AKI were septic shock, post major surgery, cardiogenic shock, drug toxicity and hypovolemia 37 . The cause of AKI in COVID-19 is likely to be multifactorial, including hemodynamic instability, microcirculatory dysfunction, tubular cell injury, renal congestion, microvascular thrombi and endothelial dysfunction 38 . Pathology from autopsies of patients with COVID-19 with renal failure revealed that the kidneys had varying degrees of acute tubular necrosis, diffuse proximal tubule injury with the loss of brush border, non-isometric vacuolar degeneration, hemosiderin granules and pigmented casts 39,40 .We found out that incidence of AKI in all hospitalized COVID-19 patients was 12.0%. The diversity of patients included in our meta-analysis cause the heterogeneity. According to the subgroup analysis, the estimated AKI incidence of patients with averaged age more than 60 years old is higher than patients averaged age less than 60 years old (13% vs 8%). Many reports on COVID-19 have highlighted age-related differences in health outcomes, mortality of COVID-19 is particularly high among older patients 41,42 . Age is also an important risk factor for AKI 43 . The pooled estimated AKI incidences in the Asian subgroup was lower than Western subgroup (8% vs 28%). Black race is a risk factor for AKI 44 .
In a large cohort study of hospitalization COVID-19 patients among black patients and white patients with COVID-19, 76.9% of the patients who were hospitalized with COVID-19 and 70.6% of those who died were black, whereas blacks comprise only 31% of the population 45 .
The incidence of AKI in ICU patients with the COVID-19 was particularly high range from 8%-62% 15,18,23-25,28,29 . Critical ill patients hospitalized with COVID-19, requiring ventilator is more likely to develop AKI 4 . In our subgroup study, patients were divided into two groups according to the proportion of using ventilator or ICU. The incidence of AKI is higher in more severe patients (24% vs 6%).
As the ongoing pandemic of COVID-19, there is an urgent need to identify safe and effective treatment options, such as antiviral drug.
Introduction of antiviral drugs is a common cause of drug-induced AKI 46,47 . In the clinical experiment of Remdesivir, AKI as the most frequent adverse event lead to drug discontinuation 11,12 . Antiviral drugs cause AKI by many mechanisms including direct renal tubular toxicity, allergic interstitial nephritis, and crystal nephropathy 48,49 . But in animal models, Remdesivir treatment was effective against MERS-CoV and did not show any side effect of AKI 50 . As shown in Figs. 2 and 3, the incidence of AKI in hospitalized COVID-19 patients using Remdesivir is lower than all hospitalized COVID-19 patients whether using Remdesivir or not. The meta-analysis of RCTs also proved that Remdesivir did not increase the risk of AKI in hospitalized COVID-19 patients. Similar to the results of our study, a RCT study of Ebola virus disease (EVD) therapeutics also showed that Remdesivir reduced mortality from EVD without increase the risk of AKI 7 . Our meta-analysis may provide an evidence for future study that AKI is associated with the natural cause of COVID-19, not the adverse event after the usage of the drug.
Our meta-analysis had some limitations. First, most of the studies included in were retrospective cross-sectional study, although most of them (72%) were high quality. The RCTs included in our study were high quality but with limited amount. Sensitivity analysis which performed using one by one exclusion got similar results in our study. Second, there was a statistically signi cant heterogeneity in the meta-analysis of AKI incidence. Acquisition, analysis, or interpretation of data: ZX and JC.
Drafting of the manuscript: ZX and YT.
Critical revision of the manuscript: AX and JC.
Statistical analysis: QH, SF, XL and BL.
All authors have read and approved the manuscript.

Competing Interests
The authors declare that they have no competing interests.  Forest plot and meta-analysis of incidence of AKI in hospitalized COVID-19 patients. Forest plot and meta-analysis of AKI incidences in hospitalized COVID-19 patients using Remdesivir.