*2.1. Bacteremia*

How do periodontal bacteria move via the blood stream and damage multiple organs? First, gingival ulceration in the periodontal pocket enables bacteria to enter the systemic circulation [29]. Recirculating leukocytes engulf and destroy foreign antigens in the immune response; however, some periodontal disease bacteria, such as *P. gingivalis* and *Actinobacillus actinomycetemcomitans*, can survive intracellularly, and may exploit macrophages and/or dendritic cells as vehicles, much like a Trojan horse, which causes silent systemic inflammation [29]. Although it remains unknown as to whether periodontal bacteria proliferate on blood vessel walls, components of periodontitis bacteria have been detected in arteriosclerotic lesions [30]. Thus, bacteremia is an important step in the progression to systematic inflammation in patients with periodontal diseases. In fact, blood bacteria levels were higher in patients with periodontitis than in those with gingivitis (*p* < 0.0001), and its level was positively associated with worse periodontal parameters [31].

### *2.2. Cytokines and Inflammation-Related Molecules*

The biological activity observed in periodontal lesions has suggested that various cytokines are involved in the pathogenesis of periodontal disease [32]. Numerous cytokines are known to be associated with periodontal disease, and cytokines are categorized by their function. Representative inflammatory cytokines include IL-1, IL-6, IL-8, and TNF-<sup>α</sup>. These inflammatory cytokines enhance vascular permeability, which may enhance bacteremia and stimulate fibroblasts and inflammatory cells, which in turn induce other cytokines. They also enhance the expression of endothelial adhesion molecules, such as intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1, E-selectin, and chemokines such as monocyte chemoattractant protein (MCP)-1 and IL-8 [33]. In addition, inflammatory cytokines regulate bone resorption and inhibit bone formation, which are associated with the local expansion of periodontal lesions through alveolar bone loss [32] and systemically with CKD-mineral bone disorder (CKD-MBD). Fibroblast growth factor (FGF)-23, which has been suggested to have a central role in CKD-MBD and in the regulation of serum phosphorus

levels, has been associated with higher inflammatory cytokine levels [34]. Moreover, inflammatory cytokines cause an expansion of the mesangial matrix or induce interstitial fibrosis [35]. If bacteremia does not cause direct damage through in situ inflammatory cytokine production in the targeted organ, increased inflammatory cytokines in local periodontal lesions cause systematic inflammation via the blood stream. Other important cytokines are growth factors, such as FGF, platelet-derived growth factor (PDGF), and transforming growth factor-β (TGF-β). Connective tissue growth factor (CTGF), which normally maintains tissue homeostasis, can induce fibrosis during the inflammatory response. Renal fibrosis has a negative impact on renal prognosis, especially in patients with CKD. Considering these findings, cytokines in periodontal diseases increase vascular permeability, enhance the expression of adhesion molecules, and cause up-regulation of TGF-β. These responses may be associated with proteinuria via glomerular permeability, renal thrombosis, and renal fibrosis, respectively, and result in a deterioration of renal function [35,36].

Periodontal disease, which is associated with systemic disorders, is associated with gram-negative organisms such as *P. gingivalis,* rather than gram-positive organisms. Generally, gram-positive cocci and rods are primarily detected in subgingival plaques of healthy people. However, in plaques formed in the gingival pocket of chronic periodontitis patients, gram-negative anaerobic bacilli increase resulting in the transition to bacterial flora, which cause the formation of more complex pathogenic plaques [37]. Lipopolysaccharides (LPS) derived from the periodontal pathogens will be delivered systemically in blood vessels to other organs. An increase in inflammation through Toll-like receptor 2 and/or 4 in the innate immune system will be observed in these organs [29]. The interaction between LPS and toll-like receptors is quite complicated: The toll-like receptor-mediated pathogenic action of LPS in the immune system di ffers depending on the derived pathogens and the toll-like receptors [38]. For example, LPS derived from *P. gingivalis* has been associated with inducing urinary protein via Toll-like receptor 2 of the renal glomerular vascular endothelial cells and the progression of kidney diseases via Toll-like receptor 4 signaling in a diabetic animal model [39]. Nonetheless, it should be noted that the downstream signaling of Toll-like receptors has crucial roles in inflammation [32].
