Renal Failure

ISSN: 0886-022X (Print) 1525-6049 (Online) Journal homepage: www.tandfonline.com/journals/irnf20
The use of Tocilizumab in COVID-19 critically ill patients with renal impairment: a multicenter, cohort study
Ohoud Aljuhani, Khalid Al Sulaiman, Ghazwa B Korayem, Aisha Alharbi, Ali F. Altebainawi, Shatha A. Aldkheel, Sarah G. Alotaibi, Ramesh Vishwakarma, Hanan Alshareef, Samiah Alsohimi, Mashael AlFaifi, Abdulrahman Al Shaya, Haifa A. Alhaidal, Raghad M. Alsubaie, Hessah Alrashidi, Khalid J. Albarqi, Dalal T. Alangari, Reem M. Alanazi, Noora M. Altaher & Hasan M. Al-Dorzi
To cite this article: Ohoud Aljuhani, Khalid Al Sulaiman, Ghazwa B Korayem, Aisha Alharbi, Ali F. Altebainawi, Shatha A. Aldkheel, Sarah G. Alotaibi, Ramesh Vishwakarma, Hanan Alshareef, Samiah Alsohimi, Mashael AlFaifi, Abdulrahman Al Shaya, Haifa A. Alhaidal, Raghad M. Alsubaie, Hessah Alrashidi, Khalid J. Albarqi, Dalal T. Alangari, Reem M. Alanazi, Noora M. Altaher & Hasan M. Al-Dorzi (2023) The use of Tocilizumab in COVID-19 critically ill patients with renal impairment: a multicenter, cohort study, Renal Failure, 45:2, 2268213, DOI: 10.1080/0886022X.2023.2268213
To link to this article: https://doi.org/10.1080/0886022X.2023.2268213
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RENAL FAILURE
2023, VOL. 45, NO. 2, 2268213 https://doi.org/10.1080/0886022X.2023.2268213
CLINICAL STUDY
The use of Tocilizumab in COVID-19 critically ill patients with renal impairment: a multicenter, cohort study
Ohoud Aljuhania, Khalid Al Sulaimanb,c,d,e, Ghazwa B Korayemf, Aisha Alharbig, Ali F. Altebainawih,i, Shatha A. Aldkheelf, Sarah G. Alotaibif, Ramesh Vishwakarmaj, Hanan Alshareefk, Samiah Alsohimil,m, Mashael AlFaifin, Abdulrahman Al Shayab,c,d, Haifa A. Alhaidalc, Raghad M. Alsubaiec, Hessah Alrashidic, Khalid J. Albarqic, Dalal T. Alangaric, Reem M. Alanazic, Noora M. Altaherc and Hasan M. Al-Dorzid,o,p
aDepartment of Pharmacy Practice, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia; bPharmaceutical Care Department, King Abdulaziz Medical City, Riyadh, Saudi Arabia; cCollege of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia; dKing Abdullah International Medical Research Center, Riyadh, Saudi Arabia; eSaudi Critical Care Pharmacy Research (SCAPE) Platform, Riyadh, Saudi Arabia; fDepartment of Pharmacy Practice, College of Pharmacy, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia; gPharmaceutical Care Department, King Abdulaziz Medical City, Jeddah, Saudi Arabia; hPharmaceutical Care Services, King Salman Specialist Hospital, Hail Health Cluster, Ministry of Health, Hail, Saudi Arabia; iDepartment of Clinical Pharmacy, College of Pharmacy, University of Hail, Hail, Saudi Arabia; jNorwich Medical School, University of East Anglia, Norwich, UK; kDepartment of Pharmacy Practice, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia; lPharmaceutical Care Services, King Fahad Armed Forces Hospital, Jeddah, Saudi Arabia; mPharmaceutical Care Services, King Abdulaziz University Hospital, Jeddah, Saudi Arabia; nPharmaceutical Care Department, King Saud Medical City, Riyadh, Saudi Arabia; oIntensive Care Department, King Abdulaziz Medical City, Riyadh, Saudi Arabia; pCollege of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia

ARTICLE HISTORY
Received 28 March 2023
Revised 3 October 2023
Accepted 3 October 2023
KEYWORDS
Tocilizumab; renal impairment; covid-19; critically ill; acute kidney injury

ABSTRACT
Tocilizumab (TCZ) is recommended in patients with COVID-19 who require oxygen therapy or ventilatory support. Despite the wide use of TCZ, little is known about its safety and effectiveness in patients with COVID-19 and renal impairment. Therefore, this study evaluated the safety and effectiveness of TCZ in critically ill patients with COVID-19 and renal impairment. A multicenter retrospective cohort study included all adult COVID-19 patients with renal impairment (eGFR˂60 mL/ min) admitted to the ICUs between March 2020 and July 2021. Patients were categorized into two groups based on TCZ use (Control vs. TCZ). The primary endpoint was the development of acute kidney injury (AKI) during ICU stay. We screened 1599 patients for eligibility; 394 patients were eligible, and 225 patients were included after PS matching (1:2 ratio); there were 75 TCZ-treated subjects and 150 controls. The rate of AKI was higher in the TCZ group compared with the control group (72.2% versus 57.4%; p = 0.03; OR: 1.83; 95% CI: 1.01, 3.34; p = 0.04). Additionally, the ICU length of stay was significantly longer in patients who received TCZ (17.5 days versus 12.5 days; p = 0.006, Beta coefficient: 0.30 days, 95% CI: 0.09, 0.50; p = 0.005). On the other hand, the 30-day and in-hospital mortality were lower in patients who received TCZ compared to the control group (HR: 0.45, 95% CI: 0.27, 0.73; p = 0.01 and HR: 0.63, 95% CI: 0.41, 0.96; p = 0.03, respectively). The use of TCZ in this population was associated with a statistically significantly higher rate of AKI while improving the overall survival on the other hand. Further research is needed to assess the risks and benefits of TCZ treatment in critically ill COVID-19 patients with renal impairment.
Introduction progress to respiratory failure, shock, and organ failure,
Coronavirus disease 2019 (COVID-2019) caused a global pan- requiring intensive care unit (ICU) admission [3,4].
demic that affected more than seven hundred million cases Severe COVID-19 cases are attributed to multiple patho- and killed more than six million people [1,2]. Patients with genesis related to the imbalance between the innate and COVID-19 may present with severe symptoms that may adaptive immunity with enhanced production of
CONTACT Khalid Al Sulaiman alsulaimankh@hotmail.com King Abdulaziz Medical City (KAMC) - Ministry of National Guard Health Affairs (MNGHA), King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, PO Box 22490, 11426 Riyadh, Saudi Arabia Supplemental data for this article can be accessed online at https://doi.org/10.1080/0886022X.2023.2268213.
© 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent.
pro-inflammatory cytokines (TNF-α, IL-1β, IL-2, and IL-6) and chemokines (IL-8) resulting in tissue injury [5–7]. The elevated level of inflammatory mediators may serve as prognosis biomarkers and has also been identified as a potential drug target for COVID-19 therapy [8]. Therefore, the use of immunomodulatory agents targeting IL-6, including Tocilizumab (TCZ) and Sarilumab, to treat severely ill patients with COVID-19 has been investigated [9].
In addition to the respiratory system, severe COVID-19 may cause multi-organ dysfunction, such as the kidney [10]. It is proposed that renal damage in patients with COVID-19 may be caused by SARS-CoV-2 direct viral damage of kidney endothelial or secondary kidney insult due to hypoxia, cytokine storm, or drug-induced nephrotoxicity. However, these causes remain debatable [11,12]. During cytokine storm, IL-6 induces renal endothelium to secrete more pro-inflammatory mediators, leading to kidney dysfunction [10,13]. Thus, the use of anti-inflammatory medications, including corticosteroids and IL-6 receptor blockers such as TCZ resulted in mortality benefits in suppressing hyper-inflammation and has been suggested by strong evidence as standard of care in severe COVID-19 [12,14–17].
TCZ is a humanized monoclonal anti-IL-6 used to treat many conditions, including critical COVID-19. Several studies evaluated its safety and efficacy in patients with COVID-19, confirming the mortality benefit and improvement in patients’ clinical outcomes [18–22]. Thus, the National Institute of Health (NIH) management guideline for COVID-19 recommends using TCZ with dexamethasone in hospitalized patients who require oxygen therapy or ventilatory support [17]. The manufacturer of TCZ recommends no dose adjustment for patients with mild to moderate renal failure [23]. At the same time, there is no specific recommendation for patients with severe renal impairment due to the lack of studies in this population [23].
Most of the previous studies assessed the effectiveness of TCZ in patients with COVID-19 regardless of their renal function [18,19]. A single-center retrospective study of critically ill patients with COVID-19 showed that adjunctive TCZ with steroids improved mortality without adversely affecting kidney function in patients on hemodialysis and non-hemodialysis [24]. The RECOVERY trial also demonstrated that using TCZ in hospitalized patients with COVID-19 with hypoxia and evidence of inflammation reduced the need for renal replacement therapy [19]. In addition, TCZ was associated with a nephroprotective effect in an animal model of sepsis-induced AKI, evidenced by improvements in various of pathological changes and a decrease in the serum creatinine and blood urea nitrogen [25]. The ACTRA-RI trial established the efficacy and safety of using TCZ in patients with rheumatoid arthritis and renal insufficiency [26].
There is limited evidence about the benefit of TCZ in critically ill patients with COVID-19 and renal impairment, in addition to a higher baseline risk of renal impairment in ICU patients [27]. The uncertainty of TCZ safety and efficacy in patients with renal impairment needs to be investigated. Therefore, the objective of our study was to assess the safety and effectiveness of TCZ in critically ill COVID-19 patients with baseline renal impairment.
Methods
Study design
This investigation is a component of the Saudi Critical Care Pharmacy Research (SCAPE) platform, which has conducted numerous studies assessing the safety and effectiveness of several therapies and interventions in critically ill patients [28]. Our current study has been designed and implemented based on the methodologies and designs employed in our previously published investigations [29–33]. We conducted a retrospective cohort study involving multiple centers (Five centers) in Saudi Arabia encompassing critically ill adult patients with COVID-19 who were admitted to intensive care units (ICUs) between March 1, 2020, and July 31, 2021. Eligible patients with renal impairment (eGFR ≤ 60) were categorized into two sub-cohorts based on Tocilizumab use (Tocilizumab versus Control). Control was defined as patients who did not receive Tocilizumab during ICU stay. The diagnosis of COVID-19 was confirmed using reverse transcriptase-polymerase chain reaction (RT–PCR), and eGFR was calculated using Modification of Diet in Renal Disease (MDRD). All eligible patients were assessed until they were discharged or died during the hospital stay.
The study was conducted in accordance with the World Medical Association Declaration of Helsinki – Ethical Principles for Medical Research Involving Human Subjects (adopted 1964; updated 2013), national ethical regulations, and local institutional guidance of study centers. The study was initially approved by the institutional review board of King Abdullah International Medical Research Center (KAIMRC) in November 2022 (Ref.# NRC22R/503/10) and then from those of other participating centers. Informed consent from the study patients was waived due to the retrospective observational nature of the study.
Study setting
This multicenter study was conducted at five centers in various Saudi Arabia regions. The selection of included centers was based on the geographic distribution, availability of data, and the center’s willingness to participate; details of participated centers can be found in the supplemental file (1).
Study Participants
The study included critically ill adult (aged ≥ 18 years) patients with COVID-19 and with a baseline estimated glomerular filtration rate (eGFR) ≤ 60 mL/min. Exclusion criteria include the use of TCZ prior to ICU admission or >24 h after ICU admission, known to have CKD requiring dialysis, patients who underwent any transplant, incomplete data/missing eGFR at baseline, death within the first 24 h of ICU

Figure 1. Flow diagram showing patients recruited with COVID-19. COVID-19: Coronavirus disease; ICU: intensive care unit; LOS: length of stay.

admission, ICU length of stay (LOS) ≤ one day, or designation as ‘Do-Not-Resuscitate’ at ICU admission (Figure 1).
Outcomes
The primary endpoint was the development of AKI during ICU stay after Tocilizumab initiation [23]. The secondary endpoints were the need for RRT (e.g., Conventional hemodialysis, CRRT), MV duration, LOS in the ICU and hospital, 30-day/ in-hospital mortality, and complication (s) that occurred during ICU stay (i.e. respiratory failure that requires mechanical ventilation, new-onset atrial fibrillation, and liver injury). The definitions of the different outcomes are detailed in Appendix A.
Data collection
The data collection tool was standardized among all centers using the Research Electronic Data Capture (REDCap®) platform hosted by King Abdullah International Medical Research Center (KAIMRC). We collected demographic information, comorbidities, vital signs, Glasgow Coma Score (GCS), severity of illness scores (Acute Physiology and Chronic Health Evaluation II (APACHE II) [34], Sequential Organ Failure Assessment (SOFA) [35], and multiple organ dysfunction scores) [36], use of prone positioning, and MV parameters (e.g., lowest PaO2/FiO2 ratio) within 24 h of ICU admission. Furthermore, the renal profile, liver function tests (LFTs), coagulation profile (i.e., International normalized ratio (INR), activated partial thromboplastin time (aPTT), fibrinogen, and D-dimer), and inflammatory markers within 24 h were collected. Additionally, the use of TCZ, dexamethasone, and nephrotoxic medications during ICU stay were recorded.
Statistical analysis
We calculated a propensity score (PS) based on predefined factors that were selected for their possible association with the study outcomes, including the patient’s age, body mass index (BMI), baseline INR, early use of dexamethasone, acute kidney injury status at admission, chronic kidney disease, and ischemic heart disease as comorbid conditions. A greedy nearest-neighbor matching method was used in which one patient who received Tocilizumab was matched with two patients in the Control group (1:2 ratio). This eventually produced the smallest within-pair difference among all available pairs with treated patients. These patients were matched only if the difference in the logits of the propensity scores for pairs of patients from the two groups was ≤ 0.1 times the pooled estimate of the standard deviation (supplementary file). The odds ratios (ORs), hazard ratios (HRs), or beta estimates with 95% confidence intervals (CIs) were reported for the outcomes using multivariable logistic, Cox proportional hazard, or negative binomial regression analyses, respectively. No imputation was made for missing data, as the cohort of patients in our study was not derived from random selection. We considered a P value of < 0.05 statistically significant and used SAS version 9.4 for all statistical analyses (Supplementary file (1)).
Results
In this study, we screened 1599 patients for eligibility from the five participating centers, and only 394 patients met the inclusion criteria. A total of 225 patients were included after PS matching (1:2 ratio): 75 patients in the TCZ group and 150 patients in the Control group. The mean dose of Tocilizumab in the active group was 5.95 ± 1.75 mg/kg. About 25.3% of the patients received multiple doses of Tocilizumab. Figure 1 presents the flowchart of the study population for the final analysis.
Demographic and clinical characteristics
Table 1 summarizes all the baseline characteristics before and after PS matching. In the whole cohort, the majority of the patients were male (60.9%), with a median age of 68.0 (58.0, 78.0) years. Hypertension (72.2%) was the most common comorbidity, followed by diabetes mellitus (70.6%) and dyslipidemia (23.5%) before PS matching. There was a statistically significant difference in the baseline characteristics between the two groups before PS matching. Patients in the TCZ group had higher BMI, dexamethasone use, use of nephrotoxic medications, and ferritin levels at baseline. In contrast, the control group has a higher white blood cells (WBCs) count, INR, and baseline PaO2/FiO2 ratio. Most of the baseline clinical characteristics and comorbidities were comparable between the groups after PS matching, except for baseline ferritin levels, Creatine phosphokinase (CPK), C-reactive protein (CRP), baseline PaO2/FiO2 ratio, and total WBCs.
AKI and the need for RRT during ICU stay
In the crude analysis after PS matching, AKI was statistically significantly higher in the TCZ group compared to the control group (72.2% versus 57.4%; p = 0.03). The severity of AKI in the TCZ group compared to the control group was as follows: (Stage 3 (51.4% vs. 36.5%), Stage 2 (8.3 vs. 10.8), and Stage 1 (12.5 vs. 10.1)). Moreover, the need for RRT among patients with AKI was higher in the TCZ group; however, it failed to reach statistical significance (43.7% versus 31.9%; p = 0.09) (Table 2).
On multivariable logistic regression analysis, patients in the TCZ group had a higher odds of AKI but a non-significant trend toward increased need for RRT (OR: 1.83; 95% CI: 1.01, 3.34; p = 0.04 and OR: 1.68; 95% CI: 0.93, 3.04; p = 0.09, respectively) (Table 2). Tocilizumab use was associated with higher odds of AKI in subgroup analysis for patients with eGFR between 31 and 60 (OR: 2.19; 95% CI: 1.05, 4.54; p = 0.04); however, it was not statistically significant for patients with eGFR ≤ 30 (OR: 1.08; 95% CI: 0.35, 3.31; p = 0.89) (Table 4). Of importance, between the two groups, there was no statistically significant difference in the use of nephrotoxic drugs or material during ICU stay (94.4% versus 89.7%; p = 0.24) (Table 1).
Mortality
The 30-day mortality was statistically significant higher in the control group compared to patients who received TCZ (63.6% vs, 46.8%; p = 0.04). Similarly, In multivariable Cox proportional hazards regression analysis, the hazard of 30-day mortality was statistically significant lower in the TCZ group (HR: 0.45, 95% CI: 0.27, 0.73; p = 0.01). The in-hospital mortality was statistically significant lower in TCZ group (HR: 0.63, 95% CI: 0.41, 0.96; p = 0.03) (Table 3). In subgroup analysis, in patients with eGFR between 31 and 60, Tocilizumab use was associated with lower 30-day mortality compared with the control group (HR: 0.39, 95% CI: 0.21, 0.74; p = 0.004). On the other hand, the 30-day and in-hospital mortality were non-significantly lower in the Tocilizumab group in subgroup analysis for patients with eGFR ≤ 30 (HR: 0.56, 95% CI: 0.26, 1.21; p = 0.14, and HR: 0.63, 95% CI: 0.32, 1.21; p = 0.18, respectively) (Table 4).
Length of stay
Patients in the TCZ group had statistical significance longer ICU LOS compared to PS-matched controls at crude analysis (17.5 days versus 12.5 days; p = 0.006) as well at regression analysis (Beta coefficient: 0.30, 95% CI: 0.09, 0.50; p = 0.005). On the other hand, there were no statistically significant differences between the two groups in hospital LOS (Beta coefficient: 0.18, 95% CI -0.03, 0.38; p = 0.09) and MV duration (Beta coefficient: 0.19, 95% CI -0.08, 0.46; p = 0.17) (Table 3).
Complications during ICU stay
Regarding other complications during ICU stay, there were no statistically significant differences between the two groups such as respiratory failure requiring MV (OR: 0.91, 95% CI: 0.25, 3.31; p = 0.89), liver injury (OR: 1.43; 95% CI: 0.62, 3.25; p = 0.39), and new-onset atrial fibrillation (OR: 1.78, 95% CI: 0.88, 3.63; p = 0.11) (Table 2).
Discussion
This multicenter retrospective study evaluated the safety and effectiveness of TCZ use in critically ill adults with COVID-19 and renal impairment (eGFR < 60 mL/min). We set the time limit for TCZ utilization to be within the first 24 hours of ICU admission because early use of TCZ was associated with lower mortality among critically ill patients [37]. Our study found significantly higher rate of AKI, longer ICU LOS, lower 30-day and in-hospital mortality among patients who received TCZ compared to the control group. The use of TCZ in critically ill COVID-19 patients was evaluated in multiple studies with varying degrees of outcomes, however none of the previous studies investigated the impact of TCZ on COVID-19 patients with renal impairment [21, 37–43]
Variable	Cohort before matching	Propensity score-matched cohort	
	Overall (N=394)	Control (N=311)	Tocilizumab (N=83)	p Value11	Overall (N=225)	Control (N=150)	Tocilizumab (N= 75)	p Value11	
Age (Years), Median (Q1, Q3)	68.0 (58.00, 78.00)	69.0 (58.00, 79.00)	67.0 (60.00, 75.00)	0.72	67.5 (58.00, 77.00)	67.5 (57.50, 78.00)	67.5 (60.00, 74.50)	0.94	
Gender - Male, η (%)	232 (60.9)	189 (62.4)	43 (55.1)	0.24	130 (59.6)	88 (59.9)	42 (59.2)	0.92	
BMI, Median (Q1, Q3)	30.0 (25.46, 34.88)	29.3 (24.97, 34.47)	31.8 (26.79, 36.33)	<0.01=	30.5 (26.22, 34.72)	30.1 (25.73, 34.60)	31.3 (26.62, 36.05)	0.20	
APACHE II score, Median (Q1, Q3)	19.0 (13.0, 28.0)	19.0 (13.0, 28.0)	18.0 (13.0, 25.5)	0.63	18.0 (12.0, 26.0)	18.0 (12.0, 26.0)	17.5 (13.0, 27.0)	0.96	
SOFA score, Median (Q1, Q3)	6.0 (4.0, 9.0)	6.0 (4.0, 9.0)	6.0 (4.0, 9.0)	0.80	6.0 (4.0, 8.0)	6.0 (4.0, 8.0)	6.0 (4.0, 9.0)	0.98	
Multiple Organ Dysfunction Score at admission, Median (Q1, Q3)	7.0 (5.0, 9.0)	7.0 (5.0, 9.0)	7.0 (5.50, 8.0)	0.83	6.0 (5.0, 8.0)	6.0 (5.0, 8.0)	7.0 (5.0, 8.0)	0.59	
Early use of dexamethasone within 24 hours of admission, η (%)	243 (62.6)	173 (56.2)	70 (87.5)	<0.01=	189 (85.9)	127 (85.8)	62 (86.1)	0.95	
Serum creatinine (pmol/L) at admission, Median (Q1, Q3)	141.0 (117.0, 227.0)	139.0 (117.0, 229.0)	154.0 (116.0, 225.0)	0.91	137.0 (114.50, 202.50)	135.0 (115.0, 189.0)	142.0 (114.0, 225.0)	0.49	
Acute Kidney Injury (AKI) within 24 hours of ICU admission, η (%)	238 (61.3)	192 (62.3)	46 (57.5)	0.42	135 (61.4)	96 (64.9)	39 (54.2)	0.12	
Mechanical Ventilation within 24 hours of ICU	300 (77.5)	238 (77.3)	62 (78.5)	0.81	180 (82.8)	123 (83.1)	57 (80.3)	0.60	
admission, η (%)									
Lowest MAP at admission, Median (Q1, Q3)	70.0 (60.0, 81.0)	70.0 (60.0, 82.67)	68.0 (60.0, 76.0)	0.27	70.0 (62.0, 83.0)	71.0 (63.0, 85.0)	68.0 (60.0, 76.0)	0.17	
Lactic acid Baseline (mmol/l), Median (Q1, Q3)	2.0 (1.34, 2.80)	2.0 (1.34, 2.72)	2.0 (1.37, 2.91)	0.66	2.0 (1.40, 2.81)	2.0 (1.40, 2.72)	2.0 (1.40, 3.03)	0.64	
Platelets count Baseline (10Λ9/Ι), Median (Q1, Q3)	247.5 (179.0 318.0)	245.0 (176.5, 318.5)	249.5 (186.0, 304.5)	0.67	253.0 (186.0, 318.0)	260.0 (186.0, 318.0)	248.0(184.5, 314.0)	0.72	
Total WBC Baseline (10Λ9/Ι), Median (Q1, Q3)	10.6 (7.33, 14.50)	11.0 (7.95, 14.95)	8.2 (6.11, 12.20)	<0.01=	10.3 (7.20, 14.90)	11.2 (8.00, 16.18)	8.1 (6.17, 12.20)	<0.01=	
International normalized ratio (INR), Median (Q1, Q3)	1.1 (1.02, 1.26)	1.1 (1.04, 1.29)	1.1 (0.99, 1.17)	<0.01=	1.1 (1.0, 1.20)	1.1 (1.0, 1.20)	1.1 (0.99, 1.17)	0.07=	
activated partial thromboplastin time (aPTT) Baseline (Seconds), Median (Q1, Q3)	31.0 (27.00, 36.70)	31.2 (27.10, 37.70)	30.8 (25.60, 33.60)	0.11	30.0 (26.25, 34.60)	29.9 (26.35, 34.85)	30.8 (25.6, 34.05)	0.84	
Total bilirubin Baseline (umol/l), Median (Q1, Q3)	9.2 (6.0, 14.80)	9.7 (6.10, 15.85)	8.1 (5.3, 13.10)	0.07	8.8 (6.0, 12.80)	8.8 (6.0, 12.5)	8.8 (5.50, 13.10)	0.93	
Alanine aminotransferase (ALT) (U/L), Median	36.0 (24.0, 60.0)	36.0 (23.5, 61.0)	37.0 (24.0, 53.0)	0.78	37.5 (24.0, 59.0)	37.5 (24.0, 60.0)	38.0 (24.0, 55.0)	0.72	
(01, Q3)									
Aspartate aminotransferase (AST) (U/L), Median (Q1,	57.0 (38.0, 88.0)	56.0 (36.0, 89.0)	59.1 (41.0, 85.0)	0.77	57.0 (37.0, 84.0)	52.0 (35.0, 82.0)	61.5 (41.0, 88.0)	0.27	
Q3)									
Albumin Baseline (gm/l), Median (Q1, Q3)	32.0 (28.0, 35.0)	32.0 (27.0, 35.0)	33.0 (30.0, 35.0)	0.28	32.0 (29.0, 35.0)	32.0 (28.0, 35.0)	32.0 (29.0, 34.50)	0.44	
Creatine phosphokinase (CPK) Baseline (U/l), Median (Q1, Q3)	205.0 (78.0, 467.0)	185.0 (76.0, 438.0)	351.0 (97.0, 589.0)	0.10	225.5 (79.50, 464.0)	204.0 (76.0, 409.0)	364.0 (175.0, 589.0)	0.04a	
C-reactive protein (CRP) Baseline (mg/l) Median (Q1,	134.0 (78.0, 221.0)	124.5 (77.0, 213.0)	161.0 (110.0, 253.0)	0.06	132.5 (81.50, 228.0)	119.0 (79.0, 221.0)	172.0 (127.0, 256.0)	0.02a	
Q3)									
Procalcitonin (ng/ml), Median (Q1, Q3)	0.7 (0.25, 1.98)	0.6 (0.25, 2.04)	0.8 (0.26, 1.70)	0.99	0.6 (0.26, 2.01)	0.5 (0.25, 2.04)	0.7 (0.26, 1.70)	0.99	
Fibrinogen Level Baseline (gm/l), Median (Q1, Q3)	5.5 (3.75, 7.27)	5.5 (3.73, 7.27)	5.2 (3.82, 6.77)	0.65	5.7 (3.88, 7.51)	5.8 (4.33, 7.58)	5.2 (3.80, 7.02)	0.28	
D-dimer Level Baseline (mg/l), Median (Q1, Q3)	1.9 (0.95, 4.27)	2.0 (1.00, 4.32)	1.9 (0.81, 3.68)	0.45	2.0 (1.01, 4.08)	2.1 (1.03, 4.30)	1.9 (0.91, 3.68)	0.62	
Ferritin Level baseline (ug/l), Median (Q1, Q3)	657.8 (388.95, 1928.5)	594.0 (382.15, 1646.5)	1052.0 (500.5, 2243.0)	0.01=	791.0 (400.0, 2001.0)	624.6 (378.0, 1581.0)	1076.0 (501.0, 2241.0)	0.01a	
Blood glucose level Baseline (mmol/l), Median (Q1, Q3) Lowest PaO2/FiO2 ratio within 24 hours of admission, Median (Q1, Q3)	12.3 (8.4, 17.10)	12.4 (8.2, 17.0)	12.3 (8.5, 17.50)	0.69	12.5 (8.7, 16.90)	13.0 (8.7, 16.90)	12.3 (9.15, 16.95)	0.87	
	81.0 (61.00, 136.10)	87.2 (64.44, 146.20)	64.5 (52.00, 95.29)	<0.01=	78.1 (57.10, 127.40)	81.6 (58.60, 137.30)	65.5 (52.0, 99.79)	0.01a	
Highest heart rate (HR) Baseline (BPM), Median (Q1, Q3)	104.0 (91.0, 118.0)	103.0 (91.0, 118.0)	104.5 (91.50, 119.5)	0.82	104.0 (93.0, 120.0)	104.0 (93.0, 120.0)	105.0 (91.0, 120.5)	0.93	
Maximum body temperature Baseline (°C), Median (Q1, Q3)	37.2 (37.0, 38.0)	37.2 (37.0, 38.0)	37.2 (37.00, 37.90)	0.36	37.3 (37.0, 38.0)	37.3 (37.0, 38.0)	37.2 (37.0, 38.0)	0.29	
Dosing of DVT prophylaxis, η (%)									
Low Dosing	55 (16.3)	47 (17.7)	8 (11.3)	0.41	23 (11.9)	17 (13.1)	6 (9.5)	0.54	
Standard Dosing	201 (59.6)	155 (58.3)	46 (64.8)		115 (59.6)	74 (56.9)	41 (65.1)		
High Dosing	81 (24.0)	64 (24.1)	17 (23.9)		55 (28.5)	39 (30.0)	16 (25.4)		
Patient received nephrotoxic drugs/material during ICU stay, η (%)c	335 (87.5)	259 (85.5)	76 (95.0)	0.02=	199 (91.3)	133 (89.7)	68 (94.4)	0.24	
Table 1. Baseline characteristics of patients admitted to the ICU.
(Continued)
RENAL FAILURE

Our study found that patients who received early TCZ had a higher rate of AKI with a twofold increased risk in multivariable logistic regression analysis, in spite of similar co-administration of nephrotoxic medications in both groups. The use of TCZ in COVID-19 patients with CKD was evaluated by Saffo et al. in a single center retrospective cohort study [44]. The study indicated that the use of renal replacement therapy was significantly greater in TCZ group than in the control group but there was no significant difference between the groups in rate the of AKI (35/54 patients [64.8%] versus 46/76 patients [60.5%]) for the overall population [44]. However, the study findings were limited by the small sample size and the low number of CKD patients [44]. The exact mechanism through which TCZ could cause AKI is unclear. However, there are a few plausible possibilities. First, TCZ may have an effect on hemodynamics by altering blood pressure and vascular tone, which may disrupt renal blood flow and contribute in the onset of AKI. Additionally, through preventing interleukin-6 (IL-6) signaling, TCZ modifies the immunological response. Inhibiting IL-6, which is involved in several inflammatory processes, may reduce kidney damage caused by the immune system. Another possibility is that TCZ has been linked in rare cases to glomerular and tubular injury due to direct renal toxicity [45, 46].
Moreover, our study found significantly longer ICU LOS in TCZ group compared to the control group which wasn’t observed in other investigations. Renal impairment has been associated with prolonged hospital stay with one study observing a median hospital LOS of 20 days for patients with preexisting history of renal impairment compared to a median of 8 days in an overall pool of COVID-19 patients, which is comparable to the median LOS in patients without renal impairment [43].
Our study observed a significantly lower 30-day mortality rate in TCZ group 46.8% versus 63.6% for controls, p = 0.04. The aforementioned retrospective study by Saffo et al. found similar mortality in TCZ and comparator groups (p = 0.76) [43]. However, data for patients with normal renal functions showed better survival outcomes with the administration of TCZ in critically ill patients with COCID-19. In line with our results, the RECOVERY trial reported a significant difference in 28-day mortality between TCZ and control group (31% vs 35%, respectively, p = 0.0028), however, patients with severe renal impairment only represented 6% of TCZ group and 5% of control group [19]. In addition, a single-center retrospective study by Toda et al. compared TCZ and steroid pulse therapy combination to standard of care in critically ill patients with COVID-19 that exhibited better survival rate with the TCZ group (100% vs 56%, p = 0.031) [19]. Of note, CKD patients represented 38% of the combination group [19]. In another retrospective cohort study by Somers et al. TCZ was compared to standard of care in mechanically ventilated patients with COVID-19 and found a statistically significant difference in 28-day mortality between the groups (14/78 patients [18%] in TCZ group versus 27/76 patients [36%] in control group, p = 0.01) (42). In the aforementioned study, CKD was the second most common comorbidity in
Table 2. Acute kidney injury and other complications during ICU after PS matching and multivariable regression.
Outcomes	Number of outcomes/ total number of
patients	Odds Ratio (95%
Control	Tocilizumab	p Value	confidence interval)	p Valuee	
Acute kidney injury (After TCZ initiation), n (%)₩ Requiring any RRT among patients with AKI, n (%) Respiratory failure requiring intubation, n (%)b New onset atrial fibrillation, n (%)c
Liver injury, n(%)Δ	85 (57.4)	52	(72.2)	0.03d	1.83	(1.01,	3.34)	0.04a
46 (31.9)	31	(43.7)	0.09d	1.68	(0.93,	3.04)	0.09
15/25 (60.0)	9/16	(56.3)	0.81d	0.91	(0.25,	3.31)	0.89
22/138 (15.9)	18/67 (26.9)	0.06d	1.78 (0.88, 3.63)	0.11
16/150 (10.8)	11/ 75(15.3)	0.34d	1.43 (0.62, 3.25)	0.39	
aSignificant if p-value <0.05.
bDenominator of the percentage is the number of patients who were not intubated within 24 h of ICU admission.
cDenominator of the percentage is the number of patients without Atrial fibrillation as comorbid condition.
dChi-square test is used to calculate the p-value.
eLogistic regression is used to calculate odds ratio and p-value.

Table 3. The outcomes of critically ill patients with COVID-19 after Propensity score matching.
Outcomes	Number of outcomes/Total number of
patients	Beta Coefficient estimate (95%
Control	Tocilizumab	p Value	confidence interval)	p Valued	
MV duration (Days), Median (Q1, Q3)
ICU Length of Stay (Days), Median (Q1, Q3)
Hospital Length of Stay (Days), Median (Q1, Q3)	11.0 (5.00, 19.00)	10.5	(5.00, 25.00)	0.27b	0.19 (-0.08 ,0.46)	0.17
12.5 (7.00, 20.00)	17.5	(9.00, 32.00)	0.006a,b	0.30 (0.09 ,0.50)	0.005a
19.0 (11.00, 26.00)	23.5	(12.00, 36.00)	0.05b	0.18 (-0.03 ,0.38)	0.09	
30-day mortality, n (%)
In-hospital mortality, n (%)	Hazard Ratio (95%	p Valuee
confidence interval)
82 (63.6)	22 (46.8)	0.04a,c	0.45 (0.27, 0.73)	0.01a
90 (69.2)	31 (63.3)	0.44c	0.63 (0.41, 0.96)	0.03a	
aSignificant if p-value <0.05.
bWilcoxon rank sum test is used to calculate the p-value.
cChi-square test is used to calculate the p-value.
dGeneralized linear model is used to calculate estimates and p-value.
eCox proportional hazards regression analysis used to calculate HR and p-value.

Table 4. Sub-group analysis based on the eGFR after PS matching.
eGFR less than or equal 30	Control	Tocilizumab	p Value	Odds Ratio (95% confidence interval)	p Valuec	
Acute kidney injury, n (%)	39/50 (78.0)	22/28 (78.6)	0.95b	1.08 (0.35 ,3.31)	0.89	
				Hazard Ratio (95% confidence interval)	p Valued	
30-day mortality, n (%)	30/45 (66.7)	9/18 (50.0)	0.22b	0.56 (0.26, 1.21)	0.14	
In-hospital mortality, n (%)	34/45 (75.6)	13/18 (72.2)	0.78e	0.63 (0.32, 1.24)	0.18	
eGFR between 31 and 60	Control	Tocilizumab	p Value	Odds Ratio (95% confidence interval)	p Valuec	
Acute kidney injury, n (%)	47/100 (47.5)	30/44 (68.2)	0.02b	2.19 (1.05 ,4.54)	0.04a	
				Hazard Ratio (95% confidence interval)	p Valued	
30-day mortality, n (%)	53/85 (62.4)	13/29 (44.8)	0.09b	0.39 (0.21, 0.74)	0.004a	
In-hospital mortality, n (%)	57/86 (66.3)	18/31 (58.1)	0.41b	0.60 (0.35, 1.04)	0.07	
aSignificant if p-value <0.05.
bChi-square test is used to calculate the p-value.
cLogistic regression is used to calculate odds ratio and p-value.
dCox proportional hazards regression analysis used to calculate HR and p-value. eFisher Exact test is used to calculate the p-value.

their cohort representing 42% of the included patients. Conversely, in a meta-analysis of multiple RCTs with mixed population, TCZ was shown to reduce mortality by 11% compared to standard of care treatment when used for COVID-19 patients [43].
Regarding other ICU complications during stay, this study showed no statistically significant differences between the two groups in ICU complications including respiratory failure requiring intubation, liver injury, new onset atrial fibrillation. On the other hand, the REMAP CAP showed that TCZ was superior to control in terms of respiratory support-free days (adjusted OR: 1.73, 95% CI: 1.31, 2.27) [8]. Aliging with mixed patient data from previous RCTs, our data indicate no difference in other reported ICU complications [21,37–39,41–43].
To our knowledge, this is the first study that investigates TCZ safety and effectiveness in critically ill adults with COVID-19 and baseline renal impairment. However, our study had some limitations. First, despite the utilization of multivariable regression analysis adjustment after propensity score matching in our study to control for confounders, the retrospective observational nature of the study still carries the risk of residual confounders. Second, we did not have data on IL-6 level due to its limited availability in the participating centers. Third, no adjustment was done for fluid therapy in our cohort which might impact on some of AKI reated outcomes. Fourth, the relatively short duration of follow-up can limit the assessment of long-term complications. Lastly, institutional and national treatment protocols were subjected to dynamic changes as evidence emerged over time which could affect TCZ prescribing in critically ill COVID-19 patients, which continued to change with the emergence of new data.
Conclusion
This multicenter cohort study evaluated critically ill COVID-19 patients with baseline renal impairment and found that the use of TCZ was associated with a significantly higher rate of AKI but a no-significant differences in the need for RRT while improving the overall survival on the other hand. These findings may suggest a potential link between TCZ and AKI in patients with lower eGFR, since the underlying mechanism for this association is unclear these results should be considered as generating hypotheses at most. Further research is needed to assess the risks and benefits of TCZ treatment in critically ill COVID-19 patients with renal impairment.
Acknowledgments
The authors thank the investigators who participated in this project from the Saudi critical care pharmacy research (SCAPE) platform.
Ethics approval and consent to participate
The study was approved in November 2022 by King Abdullah International Medical Research Center (KAIMRC) - Institutional Review Board, Riyadh, Saudi Arabia (Ref.# NRC22R/503/10). Informed consent was not required due to the research’s method as per the policy of the governmental and local research center. Participants’ confidentiality was strictly observed throughout the study by using anonymous unique serial number for each subject and restricting data only to the investigators.
Author contributions
All authors contributed to data collections, analysis, drafted, revised, and approved the final version of the manuscript.
Disclosure statement
The authors report there are no competing interests to declare.
Funding
The author(s) reported there is no funding associated with the work featured in this article.
Data availability statement
The datasets used and/or analyzed during the current study are available from corresponding author on reasonable request.
References
[1]		WHO Coronavirus (COVID-19) Dashboard. 2023. https:// covid19.who.int
[2]		Zhao J, Cui W, Tian B, et al. Efficacy of tocilizumab treatment in severely ill COVID-19 patients. Crit Care. 2020;24(1):1. doi:10.1186/s13054-020-03224-7.
[3]		Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the chinese center for disease control and prevention. JAMA. 2020;323(13):1239–11. doi:10.1001/jama.2020.2648.
[4]		Veiga VC, Prats JAGG, Farias DLC, et al. Effect of tocili- zumab on clinical outcomes at 15 days in patients with severe or critical coronavirus disease 2019: randomised controlled trial. BMJ. 2021;372:n84. doi:10.1136/bmj.n84.
[5]		Borczuk AC, Yantiss RK. The pathogenesis of coronavirus-19 disease. J Biomed Sci. 2022;29(1):87. doi:10.1186/s12929-022-00872-5.
[6]		Shekhawat J, Gauba K, Gupta S, et al. Interleukin-6 perpetrator of the COVID-19 cytokine storm. Indian J Clin Biochem. 2021;36(4):440–450. doi:10.1007/s12291-021- 00989-8.
[7]		Chen X, Zhao B, Qu Y, et al. Detectable serum SARS-CoV-2 viral load (RNAaemia) is closely correlated with drastically elevated interleukin 6 (IL-6) level in critically ill COVID-19 patients. Clin Infect Dis. 2020;71(8):1937–1942. doi:10.1093/cid/ciaa449.
[8]		Du F, Liu B, Zhang S. COVID-19: the role of excessive cytokine release and potential ACE2 down-regulation in promoting hypercoagulable state associated with severe illness. J Thromb Thrombolysis. 2021;51(2):313–329. doi:10.1007/s11239-020-02224-2.
[9]		Interleukin-6 receptor antagonists in critically ill patients with covid-19. New Eng J Med. 2021;384(16):1491–1502. doi:10.1056/NEJMoa2100433.
[10]		Faour WH, Choaib A, Issa E, et al. Mechanisms of COVID-19-induced kidney injury and current pharmacotherapies. Inflamm Res. 2022;71(1):39–56. doi:10.1007/ s00011-021-01520-8.
[11]		Ahmadian E, Hosseiniyan Khatibi SM, Razi Soofiyani S, et al. Covid-19 and kidney injury: pathophysiology and molecular mechanisms. Rev Med Virol. 2021;31(3):e2176. doi:10.1002/rmv.2176.
[12]		Legrand M, Bell S, Forni L, et al. Pathophysiology of COVID-19-associated acute kidney injury. Nat Rev Nephrol. 2021;17(11):751–764. doi:10.1038/s41581-021- 00452-0.
[13]		Desai TR, Leeper NJ, Hynes KL, et al. Interleukin-6 causes endothelial barrier dysfunction via the protein kinase C pathway. J Surg Res. 2002;104(2):118–123. doi:10.1006/ jsre.2002.6415.
[14]		Horby P, Lim WS, Emberson JR, RECOVERY Collaborative Group., et al. Dexamethasone in hospitalized patients with covid-19. N Engl J Med. 2021;384(8):693–704. doi:10.1056/NEJMoa2021436.
[15]		Tomazini BM, Maia IS, Cavalcanti AB, et al. Effect of dexamethasone on days alive and Ventilator-Free in patients with moderate or severe acute respiratory distress syndrome and COVID-19: the CoDEX randomized clinical trial. JAMA. 2020;324(13):1307–1316. doi:10.1001/ jama.2020.17021.
[16]		Sterne JAC, Murthy S, Diaz JV, WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group., et al. Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19: a meta-analysis. JAMA. 2020;324(13):1330–1341. doi:10.1001/jama.2020.17023.
[17]		Ghosn L, Chaimani A, Evrenoglou T, et al. Interleukin-6 blocking agents for treating COVID-19: a living systematic review. Cochrane Database Syst Rev. 2021;3(3):CD013881. doi:10.1002/14651858.CD013881.
[18]		Interleukin-6 receptor antagonists in critically ill patients with covid-19. N Engl J Med. 2021;384(16):1491–1502. doi:10.1056/NEJMoa2100433.
[19]		Abani O, Abbas A, Abbas F, et al. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. The Lancet. 2021;397(10285):1637–1645. doi:10.1016/S0140- 6736(21)00676-0.
[20]		Alkofide H, Almohaizeie A, Almuhaini S, et al. Tocilizumab and systemic corticosteroids in the management of patients with COVID-19: a systematic review and Meta-Analysis. Int J Infect Dis. 2021;110:320–329. doi:10.1016/j.ijid.2021.07.021.
[21]		Gupta S, Padappayil RP, Bansal A, et al. Tocilizumab in patients hospitalized with COVID-19 pneumonia: systematic review and meta-analysis of randomized controlled trials. J Investig Med. 2022;70(1):55–60. doi:10.1136/jim-2021-002001.
[22]		Rubio-Rivas M, Forero CG, Mora-Luján JM, et al. Beneficial and harmful outcomes of tocilizumab in severe COVID-19: a systematic review and meta-analysis. Pharmacotherapy: the Journal of Human Pharmacology and Drug Therapy. 2021;41(11):884–906. doi:10.1002/ phar.2627.
[23]		ACTEMRA (tocilizumab) injection. 2022. https://www. accessdata.fda.gov/drugsatfda_docs/label/2017/ 125276s114lbl.pdf
[24]		Toda M, Fujii K, Yoshifuji A, et al. Clinical efficacy and safety of combination therapy of tocilizumab and steroid pulse therapy for critical COVID-19 in HD patients. Clin Exp Nephrol. 2022;26(1):75–85. doi:10.1007/s10157- 021-02126-4.
[25]		Ibrahim YF, Moussa RA, Bayoumi AMA, et al. Tocilizumab attenuates acute lung and kidney injuries and improves survival in a rat model of sepsis via down-regulation of NF-κB/JNK: a possible role of P-glycoprotein. Inflammopharmacology.	2020;28(1):215–230. doi:10.1007/s10787-019-00628-y.
[26]		Mori S, Yoshitama T, Hidaka T, et al. Effectiveness and safety of tocilizumab therapy for patients with rheumatoid arthritis and renal insufficiency: a real-life registry study in Japan (the ACTRA-RI study). Ann Rheum Dis. 2015;74(3):627– 630. doi:10.1136/annrheumdis-2014-206695.
[27]		Ronco C, Reis T, Husain-Syed F. Management of acute kidney injury in patients with COVID-19. Lancet Respir Med. 2020;8(7):738–742. doi:10.1016/S2213-2600(20)30229-0.
[28]		SCAPE Platform. Saudi Critical Care Pharmacy Research. 2023. https://www.scape-platform.com/.
[29]		Al Sulaiman K, Aljuhani O, Badreldin HA, et al. Correction: the clinical outcomes of COVID-19 critically ill patients co-infected with other respiratory viruses: a multicenter, cohort study. BMC Infect Dis. 2023;23(1):103. doi:10.1186/ s12879-023-08072-8.
[30]		Al Harthi AF, Aljuhani O, Korayem GB, et al. Evaluation of Low-Dose aspirin use among critically ill patients with COVID-19: a multicenter propensity score matched study. J Intensive Care Med. 2022;37(9):1238–1249. doi:10.1177/08850666221093229.
[31]		Hafiz A, Alkofide H, Al Sulaiman K, et al. Thromboprophylaxis in hospitalized Non-Critically ill patients with mild-to-Moderate COVID-19 infection: a systematic review and Meta-Analysis. Clin Appl Thromb Hemost. 2023;29:10760296231191123.	doi:10.1177/ 10760296231191123.
[32]		Alyami MH, Naser AY, Orabi MAA, et al. Epidemiology of COVID-19 in the kingdom of Saudi Arabia: an ecological study. Front Public Health. 2020;8:506. doi:10.3389/ fpubh.2020.00506.
[33]		Korayem GB, Aljuhani O, Altebainawi AF, et al. The safety and effectiveness of tocilizumab in older adult critically ill patients with COVID-19: a multicenter, cohort study. Int J Infect Dis. 2022;122:252–259. doi:10.1016/j. ijid.2022.05.038.
[34]		Knaus WA, Draper EA, Wagner DP, et al. APACHE II: a severity of disease classification system. Critical Care Medicine. 1985;13(10):818–829. doi:10.1097/00003246- 198510000-00009.
[35]		Vincent JL, Moreno R, Takala J, et al. The SOFA (sepsis-related organ failure assessment) score to describe organ dysfunction/failure. On behalf of the working group on Sepsis-Related problems of the european society of intensive care medicine. Intensive Care Med. 1996;22(7):707–710. doi:10.1007/BF01709751.
[36]		Marshall JC, Cook DJ, Christou NV, et al. Multiple organ dysfunction score: a reliable descriptor of a complex clinical outcome. Crit Care Med. 1995;23(10):1638–1652. doi:10.1097/00003246-199510000-00007.
[37]		Gupta S, Wang W, Hayek SS, et al. Association between early treatment with tocilizumab and mortality among critically ill patients with COVID-19. JAMA Intern Med. 2021;181(1):41–51. January 1) doi:10.1001/jamainternmed. 2020.6252.
[38]		Morrison AR, Johnson JM, Griebe KM, et al. Z. R. (2020). clinical characteristics and predictors of survival in adults with coronavirus disease 2019 receiving tocili- zumab. J Autoimmun. 2020;114:102512. doi:10.1016/j. jaut.2020.102512.
[39]		Xu X, Han M, Li T, et al. Effective treatment of severe COVID-19 patients with tocilizumab. Proc Natl Acad Sci U S A. 2020;117(20):10970–10975. doi:10.1073/pnas.2005615117.
[40]		Rosas IO, Bräu N, Waters M, et al. Tocilizumab in Hospitalized Patients with COVID-19 Pneumonia. N Engl J Med 2020; 384:1503–1516. doi:10.1101/2020.08.27.20183442.
[41]		Salvarani C, Dolci G, Massari M, et al. Effect of tocilizum- ab vs standard care on clinical worsening in patients hospitalized with COVID-19 pneumonia. JAMA Intern Med. 2021;181(1):24–31. January 1) doi:10.1001/jamaint- ernmed.2020.6615.
[42]		Hermine O, Mariette X, Tharaux PL, et al. Effect of tocili- zumab vs usual care in adults hospitalized with COVID-19 and moderate or severe pneumonia: a randomized clinical trial. JAMA Intern Med. 2021;181(1):32– 40. doi:10.1001/jamainternmed.2020.6820.
[43]		Piscoya A, Parra Del Riego A, Cerna-Viacava R, et al. Efficacy and harms of tocilizumab for the treatment of COVID-19 patients: a systematic review and meta-analysis. PLoS One. 2022;17(6):e0269368. doi:10.1371/journal.pone.0269368.
[44]		Saffo Z, Guo W, Springer K, et al. The role of tocilizumab therapy in critically ill patients with severe acute respiratory syndrome coronavirus 2. J Osteopath Med. 2021;121(8):705–714. doi:10.1515/jom-2020-0292.
[45]		Yokota S, Imagawa T, Takei S, et al. Guidance on using to- cilizumab for juvenile idiopathic arthritis. Modern Rheumatol. 2011;21(6):563–571. doi:10.3109/s10165-011-0464-1.
[46]		Shimamoto K, Ito T, Ozaki Y, et al. Serum interleukin 6 before and after therapy with tocilizumab is a principal biomarker in patients with rheumatoid arthritis. J Rheumatol. 2013;40(7):1074–1081. doi:10.3899/jrheum. 121389.
Appendix A
Outcomes definition
•		Acute kidney injury defined as (AKIN definition) either absolute increase in SCr of at least 26.5 μmol/L (0.3 mg/ dL) within a 48 hours’ time window or by an increase in SCr ≥ 50% (1.5× times baseline) during ICU stay.
•		Ventilator-free days were calculated as following: if the patients die within 30 days of MV, the VFDs = 0, VFDs = 30 - days after MV initiation (if the patient survived and was successfully liberated from MV), and VFDs = 0 if the patient is on MV for >30 days.
•		In-hospital mortality is defined as death occurring for any cause during the hospital stay.
•		Liver injury defined as Alanine aminotransferase (ALT) exceeds three times the normal upper limit or double in patients with elevated baseline ALT.
•		Respiratory failure defined either hypercapnic respiratory failure (PaCO2 > 50 mm Hg) or hypoxemic respiratory failure (PaO2 < 60 mm Hg with a normal or low arterial carbon dioxide tension (PaCO2) that requires mechanical ventilation.