COVID–19 And Chronic Kidney Disease: An Updated Overview Of Reviews

Abstract

1. Background

Coronavirus disease (COVID–19) has resulted in the death of more than 3.5 million people worldwide. While COVID–19 mostly affects the lungs, different comorbidities can have an impact on its outcomes. We performed an overview of reviews to assess the effect of Chronic Kidney Disease (CKD) on contracting COVID–19, hospitalization, mortality, and disease severity.

2. Methods

We searched published and preprint databases. We updated the reviews by searching for primary studies published after August 2020, and prioritized reviews that are most updated and of higher quality using the AMSTAR tool.

3. Results

We included 69 systematic reviews and 66 primary studies. Twenty-eight reviews reported the prevalence of CKD among patients with COVID–19, which ranged from 0.4 to 49.0%. One systematic review showed an increased risk of hospitalization in patients with CKD and COVID–19 (RR=1.63, 95% CI 1.03–2.58) (Moderate certainty). Primary studies also showed a statistically significant increase in hospitalization in such patients. Thirty-seven systematic reviews assessed mortality risk in patients with CKD and COVID–19. The pooled estimates from primary studies for mortality in patients with CKD and COVID–19 showed an HR of 1.48 (95% CI 1.33–1.65) (Moderate certainty), an OR of 1.77 (95% CI 1.54–2.02) (Moderate certainty) and a RR of 1.6 (95% CI 0.88–2.92) (Low certainty).

4. Conclusions

Our review highlights the impact of CKD on the poor outcomes of COVID–19, underscoring the importance of identifying strategies to prevent COVID–19 infection among patients with CKD.

5. Keywords

COVID–19 · SARS–CoV–2 · Chronic kidney disease (CKD) · Mortality · Hospitalization

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Introduction

Since its emergence in December 2019, the severe acute respiratory syndrome coronavirus 2 (SARS–CoV–2) has caused over 240 million confirmed cases and more than 5 million deaths worldwide at the time of writing [1]. The World Health Organization (WHO) declared it to be a global pandemic in March 2020. Multiple studies have assessed the association between different comorbidities and coronavirus disease 2019 (COVID–19) outcomes [2, 3]. COVID–19 preferentially affects the lungs with the potential to involve multiple organ systems, including the kidneys.

The global prevalence of chronic kidney disease (CKD) is estimated to be between 9 and 12% [4]. The incidence of CKD increases with age, and about 38% of the estimated CKD population is > 65 years of age [5]. The definition and classification of CKD were established and endorsed by the National Kidney Foundation Kidney Disease Outcomes Quality Initiative and the international Kidney Disease Improving Global Outcomes (KDIGO) guideline group which categorizes CKD into five stages based on the estimated glomerular filtration rate (eGFR) (level) with further sub–classification of stage 5 into dialysis-dependent and dialysis-independent [6]. Advanced CKD is associated with a marked increase in the risk of all–cause mortality and morbidity [7]. Cardiovascular causes are estimated to account for 50% of the mortality in patients with CKD, while infections are recognized as a leading cause of non–cardiovascular morbidity and mortality in patients with advanced CKD [8–11].

In this updated overview of reviews, we aim to summarize the effect of CKD on different outcomes among patients with COVID–19. We reviewed available systematic reviews and large primary studies to assess COVID–19 incidence, severity, risk of hospitalization, and mortality among patients with CKD.

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Materials and methods

The protocol for this overview was published online and is available on PROSPERO (International Prospective Register of Systematic Reviews). The registration number is CRD42021227974. There were no amendments from the pre-specified criteria reported in the protocol throughout the review process. The results are reported according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines [12].

1. Inclusion and exclusion criteria

We started by conducting an overview of systematic reviews that reported COVID–19 outcomes in patients with CKD from January 1, 2020, to January 5, 2021. After searching systematic reviews, we updated the search by identifying primary studies published after August 2020, which was the date of the last search in the reviews. We included all published and unpublished studies of any design including retrospective, prospective, and cross-sectional observational studies. The review included studies of adult patients with suspected or confirmed COVID–19 who had CKD. The update focused on primary studies with more than 1000 patients with COVID–19. We excluded systematic reviews and primary studies focusing on children, pregnant women, kidney transplant recipients, and those with acute kidney injury. We prioritized the following PICO questions, which we addressed in the review:

PICO 1: What is the risk of patients with chronic kidney disease being infected by SARS–CoV2?

PICO 2: What is the risk of patients with chronic kidney disease being hospitalized for COVID–19?

PICO 3: What is the risk of severe COVID–19 disease and death amongst patients with chronic kidney disease?

2. Search strategy

The methods team searched the following electronic databases: Embase, PubMed, Epistemonikos, and Cochrane from January 1st, 2020 to January 5th, 2021. Additionally, the investigators searched MEDRXIV, SSRN, and LiTCOVID databases for preprints of unpublished reviews. The detailed search strategy is available in Appendix-1 (See Online Supplementary material). In addition, reviewers manually checked the reference lists of included studies to identify additional relevant publications. The investigators further extended the search to include primary studies that were not incorporated in the systematic reviews from September 1st, 2020 to January 10th, 2021. The investigators also included results from four registries in this review: Hilbrands 2020 [13], Holman 2020 [14], Jager 2020 [15], and Williamson 2020 [16]. Similarly, reviewers assessed the references of included primary studies to identify additional publications that were not captured in the original search.

3. Data collection

Four investigators (AA, RM, AG, SJ) independently performed title and abstract screening in pairs to identify eligible literature. When present, disagreements were resolved by a third investigator (RAM). After the full-text screening, four reviewers extracted data from the included systematic reviews independently (AA, RM, AG, SJ).

We collected the following information from each review: study characteristics (author name, region/country, study design, inclusion, and exclusion criteria), patient characteristics (number of patients with CKD, age, gender, comorbidities, and clinical setting), and CKD specifications (CKD stage and whether they included patients with end-stage kidney disease (ESKD) or not). We extracted the adjusted effect estimates when available with a 95% confidence interval (CI) including odds ratio (OR), relative risk (RR), and hazard ratio (HR) for the following outcomes: incidence of COVID–19 infection, hospitalization, severe illness, ICU admission, mechanical ventilation, mortality, and poor outcomes among patients with CKD and COVID–19 infection from both systematic reviews and primary studies.

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4. Quality and risk of bias assessment

We evaluated the quality of included systematic reviews using the modified Assessment of the methodological quality of systematic reviews (AMSTAR) tool checklist [17], and applying the following criteria: availability of a study protocol, comprehensive search strategy, list of excluded studies, and their reason for exclusion, risk of bias (RoB) assessment and evaluation of its impact, appropriate methods for statistical combination of results, and assessment of publication bias.

When more than one review addressed the same question, we prioritized reviews that fulfilled most of the following criteria: higher AMSTAR rating, peer-reviewed, recent date of literature search, use of the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) assessment. We also prioritized reviews that addressed the outcomes of interest in the most direct way. Appendix 2A (See Online Supplementary material) provides details about the AMSTAR evaluation of all included systematic reviews.

We evaluated the risk of bias in the primary studies using the Quality in Prognostic Studies (QUIPS) tool [18]. The QUIPS tool covers six domains: selection bias, attrition bias, prognostic factor and outcome measurement, confounding, and bias related to statistical analysis or presentation of results. The quality of each study was categorized as low risk, moderate risk, and high risk for each of the six domains. Appendix 2B (See Online Supplementary material) provides details about the QUIPS RoB evaluation for the included primary studies.

5. Certainty of the evidence

We assessed the certainty of the evidence using the GRADE approach [19]. This approach has four levels of certainty; very low, low, moderate, and high. Observational studies start at low certainty and can be downgraded for concerns of risk of bias, indirectness (applicability of the results to the question), inconsistency (heterogeneity between study results), imprecision, and publication bias, while it can be upgraded if there is a large effect, residual confounding effect, or dose-response gradient.

6. Statistical analysis

Quantitative and descriptive analyses were conducted. We summarized the characteristics of the included systematic reviews and primary studies. Moreover, overall ORs, HRs, and RRs, along with their respective 95% CIs of the mortality outcome in patients diagnosed with CKD versus those without CKD diagnosis and COVID–19 were calculated from the additional primary studies, and the studies included in the reviews using a random effect model when more than five studies were available. Study data was considered worthy of exploration of heterogeneity when the I 2 statistic was more than 50%. Attempts were also made to explain heterogeneity based on the patient’s clinical characteristics. We explored potential publication bias for the mortality outcome in studies through funnel plots. Reviewers eyeballed the plots to assess their symmetry. Subgroup analyses were conducted according to CKD classification status (stages 3, 4, or 5). All analyses were performed using Review Manager (RevMan) software version 5.4.

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Discussion

COVID–19 has affected millions of people worldwide. Many chronic medical diseases were reported as risk factors for increased mortality and severity of COVID–19, such as diabetes [56], hypertension, chronic obstructive pulmonary disease, malignancies, and CKD [127]. In 2019, CKD affected approximately 15.0% of patients aged 65 years or older of the US Medicare population [151]. Some of the major causes of morbidity and mortality in patients with CKD are infections, sepsis, and bacteremia [152]. Infections in patients with CKD can cause longer duration of hospitalization, [153] and the mortality rate from pneumonia in patients with CKD is higher than that of patients without CKD [154]. In our review, we gathered evidence from all systematic reviews and primary studies to report the impact of CKD on COVID–19 mortality, hospitalization, incidence, ICU admission, disease severity, and adverse outcomes. We found that patients with CKD were more likely to have worse outcomes from COVID–19 compared to patients without CKD. This could be attributed to the attenuated immune system activation of both the innate and adaptive immunity systems which lead to an increased susceptibility to infections in patients with CKD [155].

In comparison with the impact of other comorbidities on COVID–19 mortality, a meta-analysis showed that cardiovascular disease, hypertension, and diabetes were associated with increased mortality and severity of COVID–19: diabetes OR 2.50 (95% CI 1.74–3.59), and OR 2.35 (95% CI 1.80–3.06), hypertension OR 2.88 (95% CI 2.22–3.74), and OR 2.98 (95% CI 2.37–3.75), and cardiovascular disease OR 6.34 (95% CI 3.71–10.84), and OR 4.02 (95% CI 2.76–5.86), respectively for mortality and severity [156]. Another meta-analysis reported that patients with diabetes mellitus RR 1.48 (95% CI 1.02–2.15), cardiovascular diseases RR 2.25 (95% CI 1.60–3.17), malignancy RR 1.47 (95% CI 1.01–2.14), and hypertension RR 1.82 (95% CI 1.43–2.32) suffer a greater mortality risk compared to patients without these comorbidities [81].

Our findings show moderate certainty evidence that the risk of hospitalization is increased in patients with COVID–19 infection and CKD compared to those without CKD. Similar to mortality, there is an incremental increase in the risk of hospitalization with the advanced CKD stage [54]. In a case-control study that assessed risk factors associated with increased hospitalization in patients with CKD, the presence of comorbid ischemic heart disease was associated with a 3.5fold increase in admission rate (95% CI 2.14–5.9), while other factors included the presence of anemia, hypoalbuminemia, and late referral to a nephrologist [157].

The significance of CKD as an underlying condition for severe COVID–19 remains less well understood. In our review, we found one high-quality systematic review [46] and five primary studies [48, 52, 107, 145, 146] that reported an increased risk of severe COVID–19 disease in patients with CKD, with an OR ranging from 2.1 (95% CI 1.2–3.8) to 3.6 (95% CI 2.2–5.8). However, the definition of severe COVID–19 infection was not clear and likely inconsistent in all studies. In one meta-analysis, no primary study reported CKD as a risk factor for COVID–19 severity, but a significant association was found, OR 3.03 (95% CI, 1.09–8.47) when pooling of data took place [128].

It is worth noting that the results informing some of the outcomes were inconsistent among studies. For example, the effect estimates for the need for ICU admission and poor outcomes in patients with CKD and COVID–19 were inconsistent among the identified primary studies. Moreover, some inconsistencies in the inclusion of primary studies among the published reviews were noted. These discrepancies can be attributed to several possible factors, like the use of different definitions of CKD and disease severity, the use of different inclusion criteria in the systematic reviews, the difference in sample sizes and the timing of the studies, and different management and care that is provided to patients in each study. In addition, some studies did not adjust for all appropriate confounders, which may have played a role in the inconsistencies among results.

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The findings in this review and other studies have shed some light on the importance of implementing clear guidelines for the prevention and management of COVID–19 that are specific to patients with CKD. Because studies on these patients have shown an increased risk of mortality, hospitalization, and adverse outcomes of COVID–19, physicians should maintain a low threshold for hospital admission and close monitoring of patients with CKD who are not hospitalized, as well as early aggressive management to prevent complications. The findings should also guide us to prioritize patients with CKD during vaccine administration, regardless of their age and the advancement of their disease. Recent literature on vaccinated patients on maintenance hemodialysis showed that those patients have mounted an immune response to the vaccine, however, their antibody titers were lower than their controls [158, 159]. Studies examining the protective effect of the COVID–19 vaccine in CKD patients are underway.

Limitations

Some limitations to our overview of reviews could be noted. First, we relied on existing systematic reviews to identify studies published before September 2020. Given the inconsistency in studies included among the published reviews that are unexplained by the reviews’ inclusion and exclusion criteria, some primary studies may have been missed. However, due to the extensive effort in identifying large and well–done studies, it is unlikely that any major study that would have a considerable impact on the conclusions has been missed. Some of the systematic reviews and primary studies were preprints, which lack the vigilant peer–review process. Another limitation is the high risk of bias in multiple domains in the included primary studies, and some primary studies did not consistently adjust for important confounders. In addition, the methods of diagnosing chronic kidney disease and measuring different confounders were not explicitly detailed in most of the included primary studies. In the mortality outcome, study data were considered worthy of exploration of heterogeneity when the I 2 statistic was more than 50%. Attempts were also made to explain heterogeneity based on the patient’s clinical characteristics. However, due to a lack of reporting of factors that may explain heterogeneity in the included studies, we were unable to explore them for all the outcomes in our analysis.

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Sara S. Jdiaa1 · Razan Mansour2 · Abdallah El Alayli2 · Archana Gautam2 · Preston Thomas3 · Reem A. Mustafa2,4

1 Division of Nephrology, University of Toronto, Toronto, ON, Canada

2 Division of Nephrology and Hypertension, Department of Internal Medicine, Medical Center, University of Kansas, Kansas City, KS, USA

3 School of Medicine, University of Kansas, Kansas City, KS, USA

4 Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada