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Kidney Week

Abstract: PO2440

Pro-Inflammatory HLA-DRhi Intermediate Monocytes Are Increased in CKD

Session Information

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Cormican, Sarah, National University of Ireland Galway, Galway, Galway, Ireland
  • Naicker, Serika D., National University of Ireland Galway, Galway, Galway, Ireland
  • Power, Rachael, National University of Ireland Galway, Galway, Galway, Ireland
  • Negi, Neema, National University of Ireland Galway, Galway, Galway, Ireland
  • Fazekas, Barbara, National University of Ireland Galway, Galway, Galway, Ireland
  • Islam, Md Nahidul, National University of Ireland Galway, Galway, Galway, Ireland
  • Dennedy, Michael Conall, National University of Ireland Galway, Galway, Galway, Ireland
  • Griffin, Matthew D., National University of Ireland Galway, Galway, Galway, Ireland
Background

People with Chronic Kidney Disease (CKD) suffer high rates of cardiovascular disease and have high numbers of circulating intermediate monocytes (IMs). IM numbers are associated with cardiovascular risk. We previously defined novel IM subpopulations termed HLA-DRmid and HLA-DRhi IMs, of which HLA-DRhi IMs are increased in CKD. To understand how these cell populations contribute to endothelial damage in CKD we determined the functional properties of HLA-DRhi IMs.

Methods

People with CKD, age-matched patient controls (PC) and healthy volunteers (HV) were recruited. Blood samples were used for profiling of IM subpopulation number and phenotype, functional assays and serum isolation. Intracellular cytokine production, migration and endothelial adhesion assays were performed using ex vivo cells.

Results

Numbers and proportions of circulating HLA-DRhi IMs were higher in CKD compared to PC (3.0x104 vs. 1.9x104 cells/ml, p=0.007). Following LPS stimulation in vitro, HLA-DRhi IMs from both HV and CKD patients produced markedly higher amounts of TNF-α (p<0.0001) and IL-1β (p<0.0001) than other monocyte subpopulations. LPS-stimulated cytokine levels of HLA-DRhi IMs did not differ for HV vs. CKD. Surface profiling revealed that HLA-DRhi IMs expressed relatively high levels of specific chemokine receptors (CCR5, CX3CR1) and adhesion proteins (CD11a, CD11b, CD11c). Total monocyte migration toward CCL5 and CX3CL1 was increased in CKD vs. HV. Total monocyte adhesion to both resting and TNF-α-activated endothelial cells was increased in CKD vs. HV. Monocyte adhesion to TNF-α activated endothelial cells was partially dependent on CX3CR1-CX3CL1 binding. Finally, serum CX3CL1 was increased in CKD compared to PC (p=0.004) and correlated with CKD-EPI eGFR (R=0.33, p=0.002).

Conclusion

CKD-associated monocytosis is characterised by increased circulating HLA-DRhi IMs with high capacity for inflammatory cytokine production and high surface levels of specific adhesion proteins and chemokine receptors. CCL5 and CX3CL1-dependent chemo-attraction and CX3CL1-dependent endothelial adhesion of monocytes are increased in CKD. The results highlight targetable mechanistic links between intermediate monocytosis, accelerated atherosclerosis and progressive renal injury in CKD.

Funding

  • Private Foundation Support