The Impact of CKD on the Prognosis of COVID-19: A Protocol for Systematic Review and Meta-analysis

Background: COVID-19 is a serious respiratory disease currently causing a global pandemic. However, few studies have evaluated the prognosis of chronic kidney disease (CKD) patients infected with COVID-19. Given the comorbidities evident in CKD patients, we speculate that they are more likely to be susceptible to COVID-19 infection relative to healthy individuals. However, a systematic study is necessary to conrm the relationship between these two conditions. Methods: The Wanfang, China Science Journal Citation Report (VIP database), EMBASE, CNKI, Web of Science, PubMed, and Cochrane Library databases will be reviewed to identify relevant studies. The PRISMA-P and Cochrane Handbook guidelines were used to prepare a standardized table to extract data from all relevant studies in a uniform manner. Risk and quality assessment analyses will be conducted for all included studies, with Revman 5.3 and Stata 13.0 being used for all data analyses. The primary study outcome is the assessment of whether CKD is a risk factor associated with COVID-19 infection, and to establish whether CKD increases the risk of severe illness in those infected with COVID-19. Secondary outcomes include mortality rates in CKD patients with COVID-19. Results: This study approach will synthesize extant studies into a single systematic review and meta-analysis in order to establish whether or not CKD is a risk factor associated with the development of critical COVID-19 illness, and whether CKD patients are at a higher risk of being infected by COVID-19. Conclusion: These results will provide a basis for the clinical treatment of COVID-19 in those with CKD.

The Impact of CKD on the Prognosis of COVID- 19

Background
After rst emerging in China in late 2019, COVID-19 (coronavirus disease 2019), which is a respiratory infection that causes fever, fatigue, cough, dyspnea, and other symptoms (1), and which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (2), was declared a global pandemic by the WHO in March, 2020 (3). The SARS-CoV-2 virus has proven to be more transmissible than the SARS-CoV virus responsible for the SARS outbreak in 2003 (4), with over 40 million cases and 1 million deaths associated with COVID-19 throughout the world to date. There are no speci c drugs currently available to treat COVID-19, nor has a safe and effective vaccine capable of preventing this disease yet been approved.
Chronic kidney disease (CKD) is an important and highly prevalent condition that has the potential to in uence the susceptibility of populations to COVID-19. The incidence of CKD is very high, affecting over 200 million people throughout the world (5), with 2-4%, 1.8%, and 6.7% of adults in Europe, China, and the USA, respectively, suffering from stage 3-5 CKD (6). Prior evidence suggests that CKD patients are at a higher risk of COVID-19 relative to healthy individuals (7). This may be attributable to the fact that CKD patients regularly take immunosuppressive drugs, thus compromising their ability to combat novel pathogens. A Chinese expert group has posited that patients with end-stage renal disease (ESRD) are highly susceptible to COVID-19, with infection rates as high as 16%, much higher than rates in other groups (8). Owing to their immunosuppression and abnormal physiological functionality, CKD patients are also at a higher risk of complications following COVID-19 infection (9). Given that CKD patients undergo outpatient medical visits at a relatively high frequency, they are also more likely to be exposed to COVID-19 (10). As such, there is a clear need to conduct a systematic review and meta-analysis of the relationship between CKD and COVID-19.
Within the rst two months following the discovery of COVID-19 in China, 4.3% of Chinese individuals with severe COVID-19 were found to suffer from CKD (8). Due to the renal insu ciency exhibited by CKD patients, their ability to undergo treatment with certain medications is restricted, and their dosing must be tailored in an appropriate manner. One previous review found that CKD patients were excluded from approximately 50% of all registered COVID-19 clinical trials, including 52.7% of those trials testing chloroquine/hydroxychloroquine as a treatment for this disease (11). This exclusion is likely to exacerbate outcomes in CKD patients owing to a dearth of actionable clinical evidence.
Given these above factors, we believe it is essential that the association between CKD and COVID-19 be explored in depth. Our goal is to conduct a retrospective systematic review and meta-analysis in order to determine whether CKD is a risk factor associated with COVID-19 infection, and to establish whether CKD increases the risk of severe illness in those infected with COVID-19.

Registration
This study has applied for a registration number (CRD42020216330) on th e international prospective register of systematic reviews (PROSPERO: https://w ww.crd.york.ac.uk/PROSPERO/) database. This study will be conducted as per t he Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRIS MA-P) and the Cochrane Handbook for Systematic Review of interventions gui delines.

Types of studies
Cohort, cross-sectional, case-control, randomized controlled, and non-randomized controlled studies published in Chinese or English will all be eligible for inclusion in the present analysis. Studies will be excluded if they are reviews, meta-analysis, editorials, case-reports, lack relevant data, have a study size < 10, or contain overlapping datasets.

Participant characteristics
Study participants must meet the following criteria: 1) Patients must have been diagnosed with COVID-19 as per appropriate clinical guidelines; 2) patients must have been found to have CKD prior to COVID-19 Page 4/11 infection; 3) patients must be > 18 years old. Patients without COVID-19 will be excluded from this study.

Type of intervention
No disease interventions were de ned for this study.

Types of outcomes
Primary outcomes: This rst primary outcome will be the incidence of critical disease in analyzed patients, as de ned by the occurrence of one of the following within two weeks following COVID-19 onset: 1) respiratory failure requiring manual ventilation; 2) shock; 3) combined organ failure necessitating admission to an intensive care unit (ICU). The goal of this outcome assessment will be to determine whether CKD is a risk factor for COVID-19.
The second primary outcome will be to determine whether CKD patients are more likely to suffer from COVID-19 infection. To that end, rates of COVID-19 infection among patients with and without CKD in the included studies will be compared based upon the results of reverse-transcription polymerase chain reaction (RT-PCR) tests for SARS-CoV-2 viral RNA.

Secondary outcomes:
Mortality in patients with CKD infected with COVID19.

Search strategy
Relevant articles published through November 2020 in the Wanfang, China Science Journal Citation Report (VIP database), EMBASE, CNKI, Web of Science, PubMed, and Cochrane Library databases will be incorporated into this meta-analysis. All searches will be repeated prior to the nal analysis, and any relevant unpublished studies that can be identi ed will be incorporated as appropriate. Taking PubMed as an example, the retrieval strategy is shown in Table 1.

Screening
Studies will be screened independently by two reviewers, who will eliminate duplicate and irrelevant articles. When discrepancies arise between these two reviewers, a third investigator will be consulted (Fig.  1).

Data extraction
Data will be independently extracted from included studies by two investigators. Extracted data will include: author, year of publication, study location, study type, sample size, patient age, patient medical history, intervention time, treatment plan, and follow-up time, primary variables, and primary outcomes. Data will be compiled in a standardized spreadsheet, and discrepancies will be resolved through discussion.

Risk of bias assessment
Risk of bias for the included studies will be evaluated as per the guidelines of the Cochrane Manual 5.3.0. Seven dimensions will be assessed when gauging the risk of bias, including random sequence generation, allocation concealment, blinding protocols for patients, researchers, and outcomes assessors, incomplete outcome data, selective reporting, and other sources of bias. For each of these criteria, the risk of bias will be de ned as low, high, or unclear.

Data analysis
Review Manager 5.3 will be used to conduct this meta-analysis. Dichotomous data will be given as odds ratios (ORs) and risk ratios (RRs), while continuous data will be determined using weighted mean deviations (WMDs) or standardized mean deviations (SMDS).
2.8. Assessment of heterogeneity P-value and I 2 statistics will be used to assess study heterogeneity, with signi cant heterogeneity being de ned by P < 0.01 and I 2 ≥ 50%. Fixed-effects and random-effects models will be used to analyze data when heterogeneity is not and is present, respectively.

Sensitivity analysis
Sensitivity analyses will be performed to con rm the stability of our ndings, owing to the potential for differences in methodological quality among the included studies. Multiple tests will be performed as appropriate, and studies with a high risk of bias will be excluded in these analyses to evaluate their impact on overall study ndings.

Reporting bias assessment
If more than 10 studies are included in our nal analysis, funnel plots will be used to gauge the risk of reporting bias. When these plots appear asymmetric, we will endeavor to establish the reason for this outcome.

Discussion
Prior research has identi ed CKD as a risk factor associated with an increased risk of severe COVID-19 infection (12), and as an independent risk factor linked to patient mortality (13)(14) (15). Renal insu ciency, as de ned by an increase in baseline eGFR, serum creatinine, or serum urea nitrogen levels, is directly linked to COVID-19 mortality such that individuals with an eGFR < 60 ml/min/1.73m 2 were more likely to die from this disease (16)(17)(18). Age and comorbidities such as CKD have also been identi ed as potential risk factors linked to the incidence of adverse outcomes (19)(20) (21). COVID-19 patients often exhibit renal failure upon hospital admission (22), with one meta-analysis having detected acute kidney injury (AKI) in 9.87% of COVID-19 patients, making this the most common form of complication after those of the respiratory and cardiovascular systems (23). One study of contemporaneous cohorts of hospitalized patients with and without COVID-19 found that AKI was more common in the former patients (56.9%) relative to the latter (37.2%), with the risk of death being three times higher in COVID-19 patients with AKI relative to those without AKI. Patients with AKI infected by COVID-19 are also more likely to report a history of prior CKD relative to patients without AKI (24). SARS-CoV2 is able to utilize the human ACE2 protein as a receptor to infect target cells (25). As ACE2 is expressed at high levels in the kidneys, COVID-19 can readily cause acute or chronic kidney damage (23).
Proximal tubule injury, endodermatitis, and SARS-CoV-2 RNA have all been detected in postmortem renal samples from patients with severe COVID-19 (26). SARS-CoV-2 can also disrupt normal renal production of erythropoietin and vitamin D and impair blood pressure regulation (27). CKD can also cause these complications, and COVID-19 infection may further lead to their exacerbation. Together, these ndings strongly suggest that COVID-19 may directly damage the kidneys of affected patients, and kidney failure and death are accelerated by COVID-19 infection in those with a history of CKD (14).
These results, however, are not universal. For example, one study of 116 COVID-19 patients in the People's Hospital of Wuhan University revealed that AKI was no more common in those with COVID-19, and determined that this disease did not exacerbate AKI or CKD in affected patients. However, this study was limited by its small sample size and by the fact that it included just ve patients with a history of CKD (28).
Based upon these prior studies, we believe that there is likely to be a close relationship between CKD and severe COVID-19 infections. We therefore plan to study this relationship in detail. The results of this analysis will enable clinicians to better assess the prognosis of CKD patients affected by COVID-19, and will ensure that these clinicians remain cognizant of CKD history when evaluating COVID-19 patients.

Ethics and dissemination
As this is an analysis of secondary data, ethical approval is not required for the present systematic review and meta-analysis. The results of this study will be disseminated through international peer-reviewed journals 4.2 Consent for publication Not applicable

Data availability statement
The data used or analysed during the current study are available from the corresponding author on reasonable request.
The data used to support the ndings of this study are included within the article The data used to support the ndings of this study are included within the supplementary information les.