Chronic Kidney Disease is associated with an increase of Intimal Dendritic cells in a comparative autopsy study

Atherosclerotic vascular disease (ASVD) is more common and more severe in CKD patients than in the general population [1,7] and ASVD lesions grow faster in an uremic environment [8] suggesting a pathogenic link. Since inflammation seems critical in the development of ASVD pathogenesis [9], the higher incidence of ASVD in CKD could result from systemic and/or local vascular inflammation. Thus, we present a pilot study in 30 samples from abdominal aortas, obtained from 10 deceased patients (Table 1) to investigate whether the abdominal aorta from CKD patients presented features of enhanced inflammation that would justify the increase in ASVD lesions observed in these patients.

A few infiltrating CD3⁺ cells were found in the intima of aortas with adaptive intimal thickening (AIT) with their number increasing significantly in areas with pathological intimal thickening (PIT) or with fibroatheroma (FA) (Table 2), and correlating with the severity of the ASVD lesions (Figure 1A and B). These results are not surprising since inflammation seems to have a critical role in ASVD pathogenesis [9], subsequent to the development of maladaptive vascular inflammation as well as to the failure of inflammation-resolving regulatory processes in response to the deposition and modification of low-density lipoproteins within arterial walls [10].

Since Dendritic Cells (DCs) are key sensors of the innate and the adaptive arms of the immune system, we analyzed their presence in the aortic wall. There are several markers for the identification of DCs but it has been suggested that S100 is the most reliable marker for the visualization of the major portion of DC population in the human arterial intima [11]. Although S100 is not exclusively specific to DC and it is expressed by neural cells, S100 specifically identifies DC in the arterial intima because the intima and two-thirds of the internal part of the tunica media are not innervated [12]. The proportion of S100⁺ Intimal Dendritic Cells (IDCs) was also increased in progressive ASVD lesions (Table 2 and Figure 1C) and in patients with CKD (11 ± 6% of IDCs in CKD aortas vs. 5 ± 5% in aortas without CKD, p = 0.01; Figure 1E and F), suggesting a role of these cells in the pathogenesis of ASVD in CKD. Other works have detected IDCs in atherogenic susceptible regions in the aorta of rabbits and mice, in which their abundance was correlated with a genetic susceptibility of mice to ASVD [13]. On the contrary depletion of IDCs was shown to reduce intimal lipid accumulation, indicating that IDCs would be involved in the formation of nascent atherosclerotic lesions [14]. Furthermore, it has been suggested that a proinflammatory environment, such as CKD, might promote IDCs accumulation and predispose these regions to ASVD [13]. The origin of IDCs and the physiological role of IDCs in the normal aorta is still unknown. IDCs isolated from the aorta and valves of mice have the capacity to cross-present antigen to CD8⁺T cells in vitro, but the scarcity of T-cells in the aortic intima suggests that antigen presentation would not be their primary function. In this sense, it has been recently suggested that initial foam cells in early lesions would derive primarily from IDCs rather than from newly recruited monocytes [13].

AIT lesions showed scanty CD40⁺-expressing cells in the intima with their numbers increasing in areas with progressive ASVD lesions as well as in the vessels of the adventitia according to the severity of the lesions (Table 2). In addition, the proportion of CD40L⁺ infiltrating cells was increased in progressive ASVD lesions (Table 2) and CD40L⁺ expression was induced in endothelial cells of vasa vasorum suggesting an endothelial activation. These data are not surprising because the CD40/CD40L system has been already implicated in ASVD pathogenesis [15]. However, no relationship could be established with CKD in this work (Table 3).

Since NF-κB is a downstream target of CD40/CD40L signalling we analysed NF-κB activation in the progressive ASVD lesions, as well as its association with the accumulation of inflammatory cells, by using an antibody specific for the phospho-S536 form of NF-κB-p65 (see Methods). Activation of NF-κB was detected in endothelial cells (ECs), smooth muscle cells (SMCs) and lymphocytes (Figure 2A, second and third panels). Furthermore, numbers of activated NF-κB⁺ cells in the intima correlated positively with the severity of ASVD lesions (r = 0.56, p = 0.003) (Figure 2), and with the percentage of CD3⁺ cells in the adventitia (r = 0.50, p = 0.008), of CD40⁺ cells (r = 0.59, p = 0.002 in the intima, and r = 0.45, p = 0.02 in the adventitia), and of CD40L⁺ cells (r = 0.44, p = 0.03 in the intima). No differences were detected in the number of activated NF-κB⁺ cells in aortas from CKD patients vs. controls without CKD.

In summary, our study showed an accumulation of infiltrated CD3⁺ lymphocytes, of CD40⁺ cells as well as an increase in the activation of NF-κB associated to progressive ASVD lesions in the abdominal aorta. The arterial wall of abdominal aorta displayed an increase number of intimal dendritic cells (IDCs) in patients with CKD suggesting a role of these cells in the pathogenesis of ASVD in CKD.