Assessment of the safety of Roxadustat for cardiovascular events in chronic kidney disease-related anemia using meta-analysis and bioinformatics

Abstract

Objective: This study compares the cardiovascular risk in anemic chronic kidney disease patients treated with Roxadustat versus erythropoietin stimulating agents (ESAs). It also explores the cardiovascular impact of Roxadustat.

Methods: We searched PubMed, EMBASE, Cochrane, Scopus, and Web of Science databases up to 13 August 2023, using terms such as "ESA," "Roxadustat," "MACE," "stroke," "death," "myocardial infarction," and "heart failure." Two researchers independently selected and extracted data based on predefined criteria. We assessed the risk of bias with the Cochrane tool and analyzed statistical heterogeneity using the Q and I2 tests. We conducted subgroup analyses by geographical region and performed data analysis with Stata 14.0 and RevMan 5.4 software. Data were sourced from the NCBI database by filtering for "Roxadustat" and "human," and differentially expressed genes were identified using R software, setting the significance at p < 0.01 and a 2-fold logFC, followed by GO enrichment analysis, KEGG pathway analysis, and protein interaction network analysis.

Results: A total of 15 articles encompassing 1,43,065 patients were analyzed, including 1,38,739 patients treated with ESA and 4,326 patients treated with Roxadustat. In the overall population meta-analysis, the incidences of Major Adverse Cardiovascular Events (MACE), death, and heart failure (HF) were 13%, 8%, and 4% in the Roxadustat group, compared to 17%, 12%, and 6% in the ESA group, respectively, with P-values greater than 0.05. In the subgroup analysis, the incidences were 13%, 11%, and 4% for the Roxadustat group versus 17%, 15%, and 5% for the ESA group, also with p-values greater than 0.05. Bioinformatics analysis identified 59 differentially expressed genes, mainly involved in the inflammatory response. GO enrichment analysis revealed that these genes are primarily related to integrin binding. The main pathways identified were the TNF signaling pathway, NF-κB signaling pathway, and lipid metabolism related to atherosclerosis. The protein interaction network highlighted IL1B, CXCL8, ICAM1, CCL2, and CCL5 as the top five significantly different genes, all involved in the inflammatory response and downregulated by Roxadustat, suggesting a potential role in reducing inflammation.

Conclusion: The meta-analysis suggests that the use of Roxadustat and ESA in treating anemia associated with chronic kidney disease does not significantly alter the likelihood of cardiovascular events in the overall and American populations. However, Roxadustat exhibited a safer profile with respect to MACE, death, and heart failure. The bioinformatics findings suggest that Roxadustat may influence integrin adhesion and affect the TNF and NF-κB signaling pathways, along with lipid and atherosclerosis pathways, potentially reducing inflammation.

Keywords: Roxadustat; cardiovascular events; erythropoietin stimulating agents; inflammatory responses; meta-analysis.

FIGURE 1

Flowchart of the literature screening process.

FIGURE 2

Risk-of-bias summary of included randomized trials using the Cochrane Risk-of-Bias Tool.

FIGURE 3

Overall group (A) and subgroup (B) forest plot of MACE events in the ESA and roxadustat groups.

FIGURE 4

Overall group (A) and Subgroup (B) forest plot of MI events in the ESA and roxadustat groups. Abbreviations: MI, myocardial infarction.

FIGURE 5

Overall group (A) and Subgroup (B) forest plot of stroke events in the ESA and roxadustat groups.

FIGURE 6

Overall group (A) and Subgroup (B) forest plot of death events in the ESA and roxadustat groups. Abbreviations: ESA, erythropoiesis-stimulating agent.

FIGURE 7

Overall group (A) and Subgroup (B) forest plots of HF events in the ESA and roxadustat groups.

FIGURE 8

Funnel plot of the included study cohorts in the ESA group and the roxadustat group.

FIGURE 9

(A–D) Sensitivity analyses of the MACE, death, MI, and stroke conclusions. Abbreviations: MACE, major adverse cardiovascular events, MI, myocardial infarction, ESA, erythropoiesis-stimulating agent.

FIGURE 10

Roxadustat-related differential genes GO enrichment analysis and KEGG pathway analysis. Panel (A) displays the biological process enrichment, panel (B) shows the molecular function enrichment, panel (C) presents the cell component enrichment, and panel (D) illustrates the KEGG pathway analysis.

FIGURE 11

Protein interaction network analysis results, with red indicating genes of upregulated proteins and blue indicating genes of downregulated proteins.