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Survival and clinical outcomes of kidney transplant recipients with coronavirus disease infection: An updated systematic review and meta-analysis

ABSTRACT The recent outbreak of the 2019 novel coronavirus disease (COVID-19) has raised a tremendous global concern among people, especially those with pre-existing comorbidities. Kidney transplant (KT) recipients represent a susceptible category of patients due to the long-term administration of immunosuppressive therapy. However, data on how COVID-19 is affecting these patients are scarce. We aim to systematically review the current findings regarding survival and clinical outcomes of KT recipients with COVID-19 infection. A comprehensive literature search was conducted from PubMed and Embase published up to May 2021. Studies reporting data on the incidence of COVID-19 infection among KT recipients were included. The primary outcomes analyzed in this study, including mortality rate, mechanical ventilation requirement, intensive care unit (ICU) admission, and acute kidney injury (AKI) occurrence, were measured as a pooled prevalence rate (PR) with 95% confidence intervals (CIs). All analyses were performed using STATA® 16. A total of 30 studies comprising 3,146 KT recipients with COVID-19 infections were included. The pooled PR of mortality among KT recipients with COVID-19 infection was 21% (95% CI, 18% to 25%), ICU admission, 24% (95% CI, 20% to 28%), mechanical ventilation, 18% (95% CI, 15% to 21%), and AKI, 48% (95% CI, 42% to 53%). Meta-regression analysis showed that age was significantly associated with a higher mortality rate (P < .01). Mortality rate associated with age and relatively poor clinical outcomes were high among KT recipients with COVID-19 infection. Further studies addressing preventive measures for this at-risk population should be encouraged.


Introduction
In December 2019, in Wuhan, China, a peculiar infection began spreading among people causing signs of pneumonia of unknown origin. Biological testing indicated that this pneumonia-like infection was caused by a novel coronavirus, which was officially referred to as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). 1 As this pandemic continues to unfold, the data show wide variations in clinical characteristics down to outcomings. This COVID-19 occurred and spread throughout China. It con-tinues to spread widely to various countries around the world. 2 To date, there have been several recommendations for communitybased health interventions from multiple organizations, and there is still much debate about the optimal COVID-19 treatment strategy.
The incidence of each individual causes various symptoms. Among them, patients with immunosuppressive conditions, especially the kidney transplant (KT) recipients focused on in this study, theoretically have a higher risk for developing critical COVID-19. This occurs because KT recipients are in a chronic state of immunosuppression and comorbidity. The impact of chronic immunosuppression on clinical and survival outcomes of COVID-19 is currently unclear as there are only limited data on COVID-19 in transplant recipients. 1,3 However, it is relevant since host inflammatory responses appear to constitute an important cause of poorly associated organ injury. 3 Even though there is a great concern on the severity of clinical manifestations and the survival outcomes of COVID-19 in the KT recipient population, published reviews evaluating the results of studies regarding this phenomenon are still limited. 4,5 Therefore, this study was made with the aim of assessing the survival and clinical outcome of transplant recipient patients with COVID-19 infection.

Material and Methods
This research followed the recommendations described in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. 6 Ethical approval was not required in this present study as its exclusive use of secondary data.

Eligibility Criteria
This review used population, intervention/exposure, comparison, and outcome (PICO) framework as summarized in Table 1. We considered eligible for the inclusion of crosssectional, cohort, case series, and case-control studies evaluat-ing in KTs with positive swab test using real-time reverse transcription-polymerase chain reaction assay for SARS-CoV-2 reporting survival and clinical outcomes of the hospitalized patients. The exclusion criteria were (1) non-English articles, (2) study reported irrelevant outcomes to our interest, or the data could not be extracted; (3) animal studies and in vitro studies; and (4) conference papers, case-report, theses, and patents.

Literature Search and Study Selection
We conducted a comprehensive literature search using PubMed, Scopus, and Embase with the search period up to May 2021, using the following keywords: COVID-19 OR Coronavirus OR SARS-CoV-2 AND Kidney Transplant recipient OR Renal Transplant recipient OR Kidney Transplantation OR Renal Transplantation. Titles and abstracts taken from database searches were screened independently by three authors (M.D.V.I.D., N.Y., and Y.P.K.) to assess their potential eligibility to be included. Relevant articles were examined in full-text for eligibility criteria. Any disagreements were resolved by evaluating the full-text articles and discussion with senior authors (Y.K.). We demonstrated the process of study search and selection in a search flow diagram.

Data Collection and Quality Assessment
To ensure standardization of data extraction from the included articles, we used piloted data extraction forms. The data collected included (1) author, (2) location of the study, (3) design of the study, (4) number of participants, (5) average age of participant, (6) time on KT, and (7) percentage of men. The primary endpoints were the prevalence of mortality, mechanical ventilation, ICU admission, and AKI. The quality assessment was performed utilizing the Newcastle-Ottawa Scale, which evaluated the selection, comparability, and outcome of the included studies. 7 We further reported the pooled prevalence with 95% confidence intervals (CIs) for studies. All data were recorded into a database manager, Microsoft Excel 2019.

Data Analysis
The data were pooled as weighted prevalence with 95% CI for the majority of a clinical outcome. We used the random-effect model if there was high heterogeneity found using the Chisquared test and I 2 statistic. High heterogeneity was described by P-value .1 in the Chi-squared test and I 2 statistic > 50%. 8 Otherwise, we used the fixed-effects Mantel-Haenszel model if there was low heterogeneity (P-value > .1 or I 2 statistic 50%). To determine the influence of study-level covariates on the effect estimate and heterogeneity, we performed univariate random-effects meta-regression with restricted maximum likelihood method using age, male gender, and time on kidney • Meta-regression analysis results showed that age was significantly associated with the rate of mortality.
transplantation as the covariate. If P-value < .05, we consider the difference to have statistical significance. To assess the small-study effects, we used the Egger's regression test with a graphical funnel plot. Stata version 16.0 (StataCorp LLC, Texas, United States) was used for data analysis. 9

Study Search and Characteristics
The study selection process was summarized in Figure 1. From the multiple database searching, we identified a total of 1,448 records. After removing the duplication, we screened 1,297 abstracts and included 30 eligible studies for the metaanalysis.  The majority of the study design was cohort with less than 100 patients. Studies were reported from multiple regions of the world, but most of them reported from Spain. The baseline characteristics and the quality assessment of the included studies were summarized in Tables 2 and 3, respectively. Studies reported similar characteristics regardless of their study location, the average age of the patients was 57 years old, and most patients were male (64.5%). Overall, the quality of the included studies was moderate, as displayed in Table 3.

Publication Bias
Visual inspection of the funnel plot appears to be qualitatively symmetrical, as shown in Figure 6, which demonstrates no evidence of publication bias. Further results for Egger's test showed no evidence of small-study effects (P ¼ .186).

Meta-Regression
Meta-regression analysis results showed that age was significantly associated with the rate of mortality (P < .01) (Figure 7). However, no significant association was observed for male gender (P ¼ .825) and time on kidney transplantation (P ¼ .655).

Discussion
This study provided the updated systematic review and metaanalysis of the survival and clinical outcomes of kidney trans-plants with COVID-19 infection compared to the previously published systematic review, which evaluated 15 studies. 5 Preliminary reports suggested good clinical outcomes in renal patients with COVID-19 infection. 40,41 However, recent studies have reported that this susceptible category population had a higher mortality rate than observed in the general population. 10,34,36 Many studies hypothesized that immunosuppression may represent additional risk factors, although specific studies are still limited. 42 Even though the patients had immunosuppression, the symptoms of kidney transplant recipients with COVID-19 infection were reported similar to the general population, including fever, dry cough, and dyspnea. 38 The global mortality rate from COVID-19 on the general population ranged from 0.7% to 10.8%, varied widely based on the location of the study. 43 In Spain, 18 solid organ transplant  44 In this review, we observed a lower mortality rate from 30 studies comprising 3,146 kidney transplants with COVID-19, with a rate of 21% (18% to 25%). This result was similar to the study focused on SOT recipients diagnosed with COVID-19. 44 Pascual et al 42 reported in their study that the fatality rate during the first 60 days after kidney transplantation was considerably higher than the mortality found outside the pandemic of COVID-19. Our meta-regression analysis reported a significant association of age with mortality, but not male gender and time on KT. This result is consistent with previous studies demonstrating mortality from COVID-19 is highly associated with age, and the age of admitted patients is likely to have a consequential impact on mortality. 45 Even though our analysis did not show a significant association between mortality and time of KT, this variable might affect disease severity. In the first months after transplantation, the full impact of immunosuppression is exerted, which leads the recipients to be at maximum risk of viral infection and severity  10 þ during this period. 42 The ICU admission rate from six studies was 21% (10-31%), comparable to the results of a metaanalysis of 37 studies focusing on ICU admission rate in the general population (26%). 46 However, this result could be biased because a study by Pascual et al 42 reported some patients with the indication for ICU refuse to be admitted. The rate of mechanical ventilation requirement among kidney transplant recipients with COVID-19 was also higher than the general population (19% vs 3.5%, respectively).
Kidney injury in COVID-19 infection was suggested to be caused indirectly by the cytokine storm. 37 However, Lubetzky et al 39 hypothesized that COVID-19 might directly affect the kidney as the SARS-CoV-2 found in the kidney and urine. A meta-analysis of 20 studies focusing on AKI incidence in the general population infected with COVID-19 showed an inci-dence rate of 8.9% (4.6% to 14.5%). 47 Our findings demonstrated a considerably higher incidence of AKI than the general population, with a rate of 44% (35% to 53%). Lubetzky et al 39 proposed the potential explanation for the higher incidence of AKI in kidney transplant recipients with COVID-19. First, the recipients already have baseline stage 2 or 3 Chronic Kidney Disease (CKD) before the infection. Second, elevated tacrolimus trough level has been observed at admission in some patients, which may have further aggravated AKI. 39 This research has a few limitations. First, most studies were conducted with relatively small sample size and a short followup period, which resulted in limited insight. Second, studies reported limited data on baseline characteristics that were not enough observation to be further analyzed. Third, studies reported varied therapeutic management, which resulted in      different clinical outcomes and produced considerable heterogeneity. The results of the studies, in general, show relatively higher mortality and poor clinical outcomes among kidney transplant recipients with COVID-19 infection. Therefore, preventive measures and adaptive treatment trials are urgently needed for this population.

Conclusion
The mortality rate associated with age and relatively poor clinical outcomes were high among kidney transplant recipients compared to general population with COVID-19 infection. Further studies addressing preventive measures for this at-risk population should be encouraged.
Peer-review: Externally peer-reviewed. Financial Disclosure: The authors declared that this study has received no financial support.