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Monocyte subpopulations and cardiovascular risk in chronic kidney disease

Abstract

Chronic microinflammation and its cellular hallmark, monocyte activation, contribute substantially to the tremendous burden of cardiovascular disease (CVD) in patients with chronic kidney diseases (CKD). Monocyte heterogeneity is widely acknowledged. Cell-surface expression of CD14 and CD16 defines three functionally and phenotypically distinct subsets of monocytes: classical (CD14++CD16) monocytes, intermediate (CD14++CD16+) monocytes, and nonclassical (CD14+CD16++) monocytes. A growing body of circumstantial evidence suggests that intermediate monocytes, in particular, contribute to the development of atherosclerosis in the general population as well as in patients with CKD. Intermediate monocytes express a unique pattern of chemokine receptors that have been implicated in atherogenesis. Moreover, this subset of monocytes is predisposed to secrete proinflammatory cytokines. Findings from epidemiological studies indicate that numbers of intermediate monocytes increase with worsening renal function, and that high cell counts predict adverse outcomes in patients undergoing dialysis as well as in patients at early stages of CKD. Based on laboratory and clinical data, intermediate monocytes are a promising therapeutic target for CVD in patients with CKD.

Key Points

  • Monocytes and macrophages have a pivotal pathophysiological role in atherogenesis

  • Heterogeneity among monocytes exists—classical (CD14++CD16) monocytes, intermediate (CD14++CD16+) monocytes and nonclassical (CD14+CD16++) monocytes can be differentiated by flow cytometry

  • Intermediate monocytes have proinflammatory features—laboratory data point to a subset-specific role of these cells in the development of atherosclerosis

  • A shift towards intermediate monocytes and nonclassical monocytes occurs in patients with chronic kidney disease (CKD); high intermediate monocyte counts predict adverse outcomes in these patients

  • Chronic microinflammation and its cellular hallmark, monocyte activation, are promising therapeutic targets for tackling cardiovascular disease in patients with CKD

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Figure 1: The role of monocytes in the initiation and progression of atherosclerosis.
Figure 2: Flow cytometric analysis demonstrating human monocyte heterogeneity.
Figure 3: The potential functional roles of monocyte subsets, as suggested by gene expression and functional studies.23,27,28,29,37,74

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Acknowledgements

The authors are grateful to K. S. Rogacev, Saarland University Medical Center, Germany, who provided critical revisions to the manuscript, and to A. M. Zawada, Saarland University Medical Center, Germany, who provided Figure 1 and Figure 3.

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All authors contributed to the review and/or editing of the manuscript before submission. G. H. Heine researched data for the article, provided a substantial contribution to the discussions of content and wrote the article. D. Fliser also contributed to discussions of content and writing the article.

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Correspondence to Gunnar H. Heine.

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Heine, G., Ortiz, A., Massy, Z. et al. Monocyte subpopulations and cardiovascular risk in chronic kidney disease. Nat Rev Nephrol 8, 362–369 (2012). https://doi.org/10.1038/nrneph.2012.41

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