What Links Chronic Kidney Disease and Ischemic Cardiomyopathy? A Comprehensive Bioinformatic Analysis Utilizing Bulk and Single-Cell RNA Sequencing Data with Machine Learning

Abstract

Chronic kidney disease (CKD) emerges as a substantial contributor to various cardiovascular disorders, including ischemic cardiomyopathy (ICM). However, the underlying molecular mechanisms linking CKD and ICM remain elusive. Our study aims to unravel these connections by integrating publicly available bulk and single-cell RNA sequencing (scRNA-seq) data. Expression profiles from two ICM datasets obtained from heart tissue and one CKD with Peripheral Blood Mononuclear Cell (CKD-PBMC) dataset were collected. We initiated by identifying shared differentially expressed genes (DEGs) between ICM and CKD. Subsequent functional enrichment analysis shed light on the mechanisms connecting CKD to ICM. Machine learning algorithms enabled the identification of 13 candidate genes, including AGRN, COL16A1, COL1A2, FAP, FRZB, GPX3, ITIH5, NFASC, PTN, SLC38A1, STARD7, THBS2, and VPS35. Their expression patterns in ICM were investigated via scRNA-seq data analysis. Notably, most of them were enriched in fibroblasts. COL16A1, COL1A2, PTN, and FAP were enriched in scar-formation fibroblasts, while GPX3 and THBS2 showed enrichment in angiogenesis fibroblasts. A Gaussian naïve Bayes model was developed for diagnosing CKD-related ICM, bolstered by SHapley Additive exPlanations interpretability and validated internally and externally. In conclusion, our investigation unveils the extracellular matrix’s role in CKD and ICM interplay, identifies 13 candidate genes, and showcases their expression patterns in ICM. We also constructed a diagnostic model using 13 gene features and presented an innovative approach for managing CKD-related ICM through serum-based diagnostic strategies.