Kidney Week

Abstract: PO2440

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

Session Information

• CKD: Inflammation, Endothelial Dysfunction, and Signaling
  November 04, 2021 | Location: On-Demand, Virtual Only
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• 2103 CKD (Non-Dialysis): Mechanisms

Authors

• Cormican, Sarah, National University of Ireland Galway, Galway, Galway, Ireland

Sarah Cormican, MBChB

• Naicker, Serika D., National University of Ireland Galway, Galway, Galway, Ireland

Serika D. Naicker,

• Power, Rachael, National University of Ireland Galway, Galway, Galway, Ireland

Rachael Power,

• Negi, Neema, National University of Ireland Galway, Galway, Galway, Ireland

Neema Negi,

• Fazekas, Barbara, National University of Ireland Galway, Galway, Galway, Ireland

Barbara Fazekas,

• Islam, Md Nahidul, National University of Ireland Galway, Galway, Galway, Ireland

Md Nahidul Islam,

• Dennedy, Michael Conall, National University of Ireland Galway, Galway, Galway, Ireland

Michael Conall Dennedy,

• Griffin, Matthew D., National University of Ireland Galway, Galway, Galway, Ireland

Matthew D. Griffin,

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-DR^mid and HLA-DR^hi IMs, of which HLA-DR^hi IMs are increased in CKD. To understand how these cell populations contribute to endothelial damage in CKD we determined the functional properties of HLA-DR^hi 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-DR^hi IMs were higher in CKD compared to PC (3.0x10⁴ vs. 1.9x10⁴ cells/ml, p=0.007). Following LPS stimulation in vitro, HLA-DR^hi 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-DR^hi IMs did not differ for HV vs. CKD. Surface profiling revealed that HLA-DR^hi 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-DR^hi 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