Background
Coronavirus disease 2019 (COVID-19) imposed a significant burden on public health. As of the 20th of November 2022, there had been 634 million confirmed cases of COVID-19 globally, including 6.6 million deaths. Almost three years after the pandemic started, some patients infected with COVID-19 were found to suffer from long-term symptoms, a condition that is referred to as “long COVID.” This discovery poses a number of new clinical challenges [
1‐
4].
Although COVID-19 is predominantly a respiratory disease, previous studies have reported a broad spectrum of kidney impairment during long COVID-19 [
5,
6]. However, whether this association is causal remains unknown. Conventional observational studies may be influenced by a range of confounding factors, including socioeconomic status and drug use; consequently, such analyses may not provide definitive answers. Using genetic variation as a tool to predict exposure, Mendelian randomization (MR) provides an efficient tool that can determine estimates that are not influenced by confounding factors without any intervention [
7‐
9]. Furthermore, investigating the distribution of single nucleotide polymorphisms (SNPs) by performing MR analysis can help to identify specific risk factors for the development of COVID-19 infection [
10,
11]. This form of analysis may help us to identify groups of patients that may be more susceptible to renal dysfunction.
In a recent MR study [
12], Zhao et al. reported that genetic predisposition to reduced estimated glomerular filtration rate (eGFR), as calculated from the serum levels of creatinine, was associated with increased susceptibility to severe COVID-19. Generally, the serum level of creatinine has become the most widely used parameter for evaluating kidney function in clinical practice [
13]. However, since the serum levels of creatinine are influenced by muscle mass or diet, the calculation of eGFR from the serum levels of cystatin C presents certain advantages when assessing kidney function [
14,
15]. Moreover, the additional trimming of SNPs is necessary to remove genetic variants that are likely to be related to creatinine metabolism instead of kidney function. Additionally, much is still unknown because of the limited number of associated single nucleotide polymorphisms (SNPs) of COVID-19 used in previous studies. It is necessary to determine the genetic association between eGFR and COVID-19 hospitalization or infection in a European population.
In the present study, we conducted an updated bidirectional MR analysis, including genome-wide summary statistics for log-eGFR, as calculated using the serum levels of creatinine or cystatin C, with a large sample size, the latest COVID-19 genome-wide association study (GWAS) data, and several sensitivity analyses, to investigate the assumptions generated by MR.
Discussion
In the present study, MR analysis demonstrated that genetically instrumented kidney dysfunction (based on eGFRcrea and eGFRcys) was related to a higher risk of severe COVID-19, COVID-19 hospitalization, and all COVID-19 cases. Our findings further support the fact that improving kidney function is likely to exert a beneficial effect on lowering the risk of COVID-19, regardless of phenotype, with significant implications for healthcare and drug repositioning. Furthermore, we revealed that COVID-19 has a complex effect on various indicators of renal function indicators, meaning that the influence of COVID-19 on renal function might be complex.
The kidneys perform a range of functions and are associated with immune responses, inflammation, coagulation, and endothelial function [
23‐
25]. The failure of renal function may result in impaired protein catabolism and the accumulation of metabolic waste products; these effects may contribute to increased inflammation and immunosuppression [
26]. Chronic kidney disease may contribute to the infection and development of COVID-19
via both direct and indirect mechanisms. Known predisposing factors include immune response dysfunction in the pre-uremic or uremic state and the loss of antibody and complement caused by glomerular damage, systemic inflammation, and immunosuppressants [
27]. In a previous study, Mehta et al. reported that the most critical feature of severe COVID-19 is cytokine storm syndrome and immunosuppression. In addition, hypercoagulation and venous thrombosis usually coexist with kidney failure [
24,
25,
28]. A previous study reported thrombin production in patients on dialysis and that this effect increased the risk of thrombosis and COVID-19 [
29]. Another study found that reduced renal function was associated with endothelial dysfunction [
23] and that this effect may also contribute to the development of severe COVID-19. However, these pathways have not been confirmed by experimental studies and cannot be evaluated by MR studies because relevant GWAS data are unavailable.
In a recent MR study [
12], Zhao et al. reported that genetic predisposition to eGFRcrea was associated with increased susceptibility to COVID-19. However, as the serum levels of creatinine are known to be influenced by muscle mass and diet, the eGFR value based on cystatin C level has certain advantages when assessing kidney function [
14,
15]. Our current findings are preliminary and need to be interpreted cautiously. The protective association of kidney function with severe COVID-19 might reflect an association that is specific to severe COVID-19, an incidental finding, or a lack of power for other COVID-19 outcomes. A previous GWAS meta-analysis of eGFRcrea data that was conducted by the CKDGen Consortium explained almost 20% of the genetic heritability of eGFRcrea [
30]. A substantial fraction of missing heritability is expected to be attributed to low-frequency and rare variants, which require even larger GWAS sample sizes. While eGFRcrea is a useful biomarker for kidney function in clinical practice, serum creatinine is a key metabolite of muscle metabolism and, thus, might reflect functions that are not specific to the kidney. It is very difficult for eGFRcrea GWAS to identify mechanisms of biomarker metabolism from modulators of kidney function. The estimation of GFR by serum cystatin C may represent a better marker of GFR. However, eGFRcys can also be influenced by factors other than GFR, such as inflammation, obesity and diabetes. Moreover, eGFRcys has a limited role in the GWAS of kidney function due to high costs and small datasets [
14,
15,
31]. Therefore, in the present study it was necessary to perform additional trimming of SNPs to remove genetic variants that were likely to be related to the metabolism of creatinine instead of kidney function.
In the present study, we conducted updated bidirectional MR analysis, including genome-wide summary statistics for log-eGFRcrea or eGFRcys with a large sample size and utilizing the very latest GWAS data relating to COVID-19. In the present study, we found that genetically instrumented better kidney function (based on lower eGFRcrea and eGFRcys values) was significantly related to a higher risk of severe COVID-19, COVID-19 hospitalization, and all COVID-19 cases. We defined severe COVID-19 as death and respiratory support following hospitalization due to COVID-19, in which hospitalization involved supplemental oxygen (not including simple supplementary oxygen), non-invasive mechanical ventilation, and invasive mechanical ventilation. The genetic associations with severe COVID-19 were derived from summary statistics; it was not possible to provide a breakdown by the mode of respiratory support. In addition, we investigated the impact of eGFR on severe COVID-19 with respiratory failure and critical COVID-19. However, due to the limited number of cases in the fourth round and the absence of phenotypic data in the seventh round of GWAS summary data for COVID-19, we were unable to acquire meaningful results. However, we found that a reduced eGFR was causally associated with an increase in the risk of COVID-19 infection and hospitalization. Therefore, our findings indicate that COVID-19 and kidney function are closely linked; this is a major problem since COVID-19 remains a persistent threat to public health across the world. The ongoing COVID-19 pandemic demands a concerted effort to develop new therapeutic strategies to prevent new infections and reduce the severity of infection in patients.
In this study, we investigated the association between COVID-19 and multiple indices of kidney function. However, we obtained inconsistent conclusions, potentially due to the influence of different metabolic pathways on the selected indices or the complex effects of COVID-19 that might lead to renal hyperfiltration or renal dysfunction. Several cross-sectional studies have demonstrated that renal hyperfiltration is associated with various medical conditions, including diabetes, hypertension, obesity, prehypertension, and prediabetes, as well as lifestyle factors, such as smoking, the lack of physical activity, and low levels of aerobic physical activity [
32‐
34]. We identified a causal association between hospitalization for COVID-19 and an increase in uACR; however, these results need to be interpreted with caution. Further analysis of specific individuals is now necessary to fully determine the effect of COVID-19 on renal function. A previous observation study reported that kidney dysfunction is common in patients with COVID-19 and may result in a progressive decline in kidney function and the onset of CKD [
35]. Thus, patients with COVID-19 and kidney impairment should be managed in an active manner to protect kidney function and minimize potential long-term effects.
Limitations
There were several limitations to this study that need to be considered. First, because the COVID-19 pandemic is ongoing and COVID19-hg GWAS meta-analyses round 7 including UK Biobank, it is inevitable that our analysis may have featured a certain overlap in samples that may have caused bias in the two-sample MR. However, our analysis included many SNP sites and our MR analysis was performed in a rigorous manner. Second, although we demonstrated the causal effect of eGFR on COVID-19, dedicated clinical trials are required to fully determine whether the risk of COVID-19 can be actually reduced via the management of kidney dysfunction. Furthermore, it is important that future studies investigate non-genetic influences and other potential confounders that were not accounted for in the present study. Third, it is possible that a non-linear causal relationship may exist between COVID-19 and the changes of eGFR; to address this, it is necessary to perform non-linear MR analysis for individual patients. Finally, our MR analysis only involved a population of patients of European ancestry; consequently, our current findings now need to be verified in populations of patients from other ancestries.
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