Chronic Kidney Disease Is Characterized by Expansion of a Distinct Proinflammatory Intermediate Monocyte Subtype and by Increased Monocyte Adhesion to Endothelial Cells

Background Cardiovascular disease (CVD) in patients with CKD is associated with increased circulating intermediate monocytes (IMs). Dysregulation of monocyte maturation and function is associated with CKD and its complications, but it is incompletely characterized. Methods To explore monocyte repertoire abnormalities in CKD, we studied properties of monocyte subpopulations, including IM subpopulations distinguished by HLA-DR expression level, in individuals with or without CKD. Using flow cytometry, we profiled monocyte populations in blood samples from adults with CKD, healthy volunteers (HVs), and patient controls (PCs) with high CVD risk. Monocyte sub populations were also derived from single-cell RNA-sequencing profiles of paired blood and biopsy samples from kidney transplant recipients. We quantified intracellular cytokine production, migration, and endothelial adhesion in ex vivo assays of PBMCs.Results Of four predefined blood monocyte subpopulations, only HLA-DRhi IMs were increased in individuals with CKD compared with HVs and PCs. In HVs and patients with CKD, LPS-stimulated HLA-DRhi IMs isolated from blood produced higher amounts of TNF and IL-1b than other monocyte populations. Single-cell analysis revealed four monocyte clusters common to blood and kidneys, including an HLA-DRhi IM-like cluster that was enriched in kidneys versus blood. Migration toward CCL5 and CX3CL1 and adhesion to primary endothelial cell layers were increased in monocyte subpopulations in individuals with CKD compared with HVs. Monocyte adhesion to endothelial cells was partly dependent on CX3CR1/CX3CL1 interaction.Conclusions CKD is associated with an increased number of a distinctive proinflammatory IM subpopulation and abnormalities of monocyte migration and endothelial adhesion. Dysregulated monocyte maturation and function may represent targetable factors contributing to accelerated CVD in CKD.

Automated summary

Cardiovascular disease (CVD) in patients with chronic kidney disease (CKD) is associated with increased levels of intermediate monocytes (IMs). Dysregulation of monocyte maturation and function may contribute to cardiovascular complications in CKD. In this study, the authors examined monocyte subpopulations and found that HLA-DRhi IMs were increased in individuals with CKD. These IMs produced higher levels of proinflammatory cytokines and showed increased migration and adhesion to endothelial cells compared to other monocyte populations. Dysregulated monocyte maturation and function may be targeted to reduce accelerated CVD in CKD.