**1. Introduction**

Chronic kidney disease (CKD) is defined as either the presence of kidney damage, such as proteinuria and hematuria, or decreased kidney function (estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m<sup>2</sup> for >3 months) [1]. CKD is a crucial health issue, as it has a negative impact on prognosis and quality of life (QoL) due to the increasing risk of various pathological conditions including hypertension, diabetes, smoking, aging, autoimmune diseases, systemic inflammation, urinary tract infections, urinary stones, lower urinary tract obstruction, recovery from acute kidney injury, low birth weight, and drug toxicity [2–5]. Conversely, several risk factors of CKD, such as hypertension, diabetes, smoking, and aging have also been identified [1]. Thus, early recognition of CKD and the prevention of CKD progression are highly desirable. Furthermore, growing research has shown that periodontal disease and CKD are positively correlated, although periodontal disease is an important risk factor for CKD as it has the potential to be modified and treated. Several cohort studies have investigated the relationship between CKD and periodontal disease [6–8]. Systematic reviews have also reported that periodontal disease is associated with CKD [9–11]. Moreover, the severity of periodontal disease is correlated with a decline in kidney function [12]. Although periodontal disease is a mixed infection, gram-negative bacilli play a major role. *Porphyromonas gingivalis* is implicated in periodontal disease, and elevated levels of immunoglobulin G (IgG) antibodies against *P. gingivalis* were shown to positively correlate with the onset and progression of CKD [13]. Despite speculations that CKD is closely associated with the occurrence and progression of periodontal disease, detailed pathological characteristics at the molecular level and the clinical significance of periodontal disease in CKD patients are not fully understood and still remain unknown.

Renal replacement therapy is performed to maintain QoL and life in patients with end-stage renal disease (ESRD). As renal replacement therapy, peritoneal dialysis, hemodialysis, and kidney transplantation (KT) are usually selected according to the patient's wishes; his/her clinical condition, the original disease, and/or the presence of transplant organ donor sources. In general, KT has some advantages in the improvement of life expectancy and QoL compared with dialytic therapies [14,15]. In fact, in contrast to peritoneal dialysis and hemodialysis, limitation of amount of drinking water and excessive dietary restriction are necessary the patients received KT when transplanted renal graft achieves normal function [16]. In addition, concentrations of uremic toxins in patients with KT are remarkably lower than those dialysis patients even though technology of dialysis is improving [17]. Such advantages are important to prevent the periodontal disease because oral health is improved by increased drinking of water and normalization of salivary properties [18,19]. Conversely, we also should note that kidney function in KT patients is usually equal to that of CKD patients because there may be still a functional contralateral kidney. Although the di fferences in renal function are limited between CKD and KT patients, KT should be considered an immunosuppressive status due to the immunosuppressive therapy required in these patients, and this immunoreactivity plays an important role in periodontal disease [20].

In this review, at first, we summarize information regarding the pathogenesis of periodontal disease to provide a better understanding of the specific pathological mechanisms of periodontal disease in CKD and KT patients. Briefly, we pay special attention to common pathological conditions in patients with periodontal diseases and in patients with CKD or KT. Based on this information, we then introduce the impact of periodontal disease on various other diseases and on the pathological status of CKD patients. Moreover, this review also reveals the clinical significance of periodontal disease in patients with KT. Specifically, we discuss the influence of immunosuppressive drugs used to treat oral pathological conditions including gingival overgrowth in patients with KT. Furthermore, we compare the periodontal pathogens implicated in CKD and KT patients. Finally, the impact of periodontal therapy on outcome of kidney function in these patients is discussed, and we comment on the importance of periodic oral care and appropriate periodontal treatment. Thus, this review provides comprehensive and cross-sectional information on the pathological roles of periodontal disease in CKD and KT, while we emphasize that a better understanding of pathogens, pathological roles, and

the impact of immunosuppressive therapy is essential to maintain the QoL, avoid complications, and improve survival in these patients.

### **2. Modulators of Periodontal Disease**

It is necessary to exacerbate inflammation in distant tissues for local inflammation of the teeth to injure distant organs. There are several mechanisms through which periodontal bacteria affect multiple organs, such as systemic bacteremia, cytokine release and inflammation, swallowing to the gastrointestinal tract, and direct exposure through alveolar bone destruction. The first two mechanisms are common pathways for multiple organ failure. Bacteremia caused by bacteria invades the blood stream through the periodontitis lesion and an influx of inflammation mediators, such as interleukin (IL)-6 and tumor necrosis factor (TNF)-<sup>α</sup>, produced in the lesion can be introduced into the systemic circulation. Importantly, the pathological significance of such processes in patients with CKD is different from that of healthy individuals. For example, case fatality rates at 30 and 90 days in ESRD patients with bloodstream infections was 15% and 25%, respectively; however, the rate in control patients was 0% [21]. In addition, a uremic environment due to CKD was reported to modulate the levels of various cytokines and inflammation-related molecules, including toll-like receptor in immune cells, leading to increased inflammation [22]. Furthermore, other investigators have paid special attention to the relationships between CKD and oxidative stress, endothelial dysfunction, and adhesion molecules [23–25]. However, these factors that may be modulated by CKD play important roles in inflammation under various physiological and pathological conditions [23,26–28]. Based on these considerations, we review previous reports describing the pathological significance of bacteremia, cytokines and inflammation-related molecules, oxidative stress, and endothelial dysfunction in periodontal disease.
