Arterial and Cellular Inflammation in Patients with CKD

Abstract

CKD associates with a 1.5- to 3.5-fold increased risk for cardiovascular disease. Both diseases are characterized by increased inflammation, and in patients with CKD, elevated C-reactive protein level predicts cardiovascular risk. In addition to systemic inflammation, local arterial inflammation, driven by monocyte-derived macrophages, predicts future cardiovascular events in the general population. We hypothesized that subjects with CKD have increased arterial and cellular inflammation, reflected by ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography computed tomography (PET/CT) of the arterial wall and a migratory phenotype of monocytes. We assessed ¹⁸F-FDG uptake in the arterial wall in 14 patients with CKD (mean±SD age: 59±5 years, mean±SD eGFR: 37±12 ml/min per 1.73 m²) but without cardiovascular diseases, diabetes, or inflammatory conditions and in 14 control subjects (mean age: 60±11 years, mean eGFR: 86±16 ml/min per 1.73 m²). Compared with controls, patients with CKD showed increased arterial inflammation, quantified as target-to-background ratio (TBR) in the aorta (TBR_max: CKD, 3.14±0.70 versus control, 2.12±0.27; P=0.001) and the carotid arteries (TBR_max: CKD, 2.45±0.65 versus control, 1.66±0.27; P<0.001). Characterization of circulating monocytes using flow cytometry revealed increased chemokine receptor expression and enhanced transendothelial migration capacity in patients with CKD compared with controls. In conclusion, this increased arterial wall inflammation, observed in patients with CKD but without overt atherosclerotic disease and with few traditional risk factors, may contribute to the increased cardiovascular risk associated with CKD. The concomitant elevation of monocyte activity may provide novel therapeutic targets for attenuating this inflammation and thereby preventing CKD-associated cardiovascular disease.

Keywords: Chronic inflammation; cardiovascular disease; chemokine receptor; chronic kidney disease.

Figure 1.

Increased arterial wall inflammation in patients with CKD. ¹⁸F-FDG uptake in the aortic arch (top) and the carotid arteries (bottom) was quantified as the TBR in controls (n=14, represented in A) and patients with CKD (n=14, represented in B). In patients with CKD uptake in the whole vessel (TBR_max) (C, E) as well as the MDS (D, F). Data are mean±SD; *P<0.05; **P<0.01. C, carotid; JV, jugular vein.

Figure 2.

Monocytes of CKD subjects show increased expression of chemokine receptors and enhanced migratory capacity. Flow cytometry on whole blood was performed to study expression of monocyte surface markers. Monocytes were divided into classic (CD14⁺⁺CD16⁻), intermediate (CD14⁺⁺CD16⁺), or nonclassic (CD14⁽⁺⁾CD16⁺) monocytes. (A) Surface expression of monocyte CCR7, CCR2, and CCR5 represented as Δ median fluorescence intensity (MFI), in CKD subjects (n=14) versus controls (n=14). (B, C, D) Transendothelial migratory capacity was quantified as the number of transmigrated cells per millimeter². (E) For each subject, transmigrated cells are calculated of independent counts of five frames of view. Data represent mean±SEM. *P<0.05; **P<0.01; ***P<0.001.