Part1: Natural Bioactive Compounds in The Management Of Oral Diseases in Nephropathic Patients

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Abstract: Among chronic non-communicable degenerative diseases (CDNCDs), chronic kidney disease (CKD) represents a global public health problem. Recent studies demonstrate a mutual cause-effect relationship between CKD and oral diseases, in which the presence of one induces the onset and faster progression of the other. In particular, the oral cavity alterations more frequent in CKD patients are chronic periodontitis diseases, bone lesions, oral infections, and oral cancer lesions. Currently, a standardized therapy for the treatment of oral diseases is lacking. For this reason, natural bioactive compounds (NBCs), characterized by several health effects, such as antioxidant, antimicrobial, anti-inflammatory, and anti-cancer actions, represent a new possible adjuvant therapy in the management of these pathological conditions. Among NBC's, polyphenols play a leading role due to positive modulation of oral microbiota, preventing and correcting oral dysbiosis. Moreover, these compounds exert anti-inflammatory effects, such as inhibiting the production of pro-inflammatory cytokines and the expression of cyclooxygenase-2. In this light, the formulation of a new mouthwash/gel/gingival paste, with a high content of polyphenols in association with NBC's characterized by antimicrobial action, could represent a future therapy for oral disease in CKD patients.

Keywords: chronic kidney disease; chronic periodontitis diseases; polyphenols; oral microbiota; renal replacement therapy; special care dentistry

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1. Introduction

Oral diseases are among the most widespread pathologies in the world and have rapid diffusion, becoming a real global epidemic in the last few years. Oral diseases are often associated with debilitating conditions that reduce the quality of life of patients and increase public health costs[1]. For this reason, over the years greater attention has been paid to oral preventive education, encouraging the use of good hygiene practices, and discouraging poor lifestyle habits, such as smoking, alcohol abuse, and excessive consumption of sugar [2,3]. Oral health appears to be closely related to an individual's overall health [4]. The onset of oral disease, for example, caries or periodontitis, seems to represent an important risk factor for the development of several chronic non-communicable degenerative diseases(CDNCDs), including chronic kidney disease(CKD)[5,6]. Several studies suggest that chronic periodontitis disease(CPD)is associated with an increased risk of diabetes mellitus, arterial hypertension, atherosclerosis,  and neurodegenerative diseases [7-13]. The oral diseases and CKDseem to be connected in a mutual cause-effect relationship, in which the presence of one induces the onset and progression of the other|14,15. Recent epidemiological studies suggest that CKD patients appear to be more predisposed to oral diseases compared to the general population [16,17]. However, the mechanisms underlying this relationship are still poorly studied and the available data need to be confirmed by larger randomized clinical trials. The possible link between the two diseases could be represented by the alteration of the oral microbiota, a set of symbiotic bacteria in the oral cavity[18]. In fact, on the one hand, oral diseases induce an alteration of the oral microbiota, which loses its ability to protect the host from pathogenic bacteria that can enter through the buccal opening. For this reason, the alteration of oral microbiota composition could represent a risk factor for the CDNCDs onset. Therefore, these systemic diseases could induce, in turn, an alteration of the oral microbiota that is associated with increased susceptibility to the oral disease onset [19,20]. Currently, one of the main topics of research is focusing on the use of strategies to prevent alterations of the oral microbiota and safeguard the host's general health[18]. In this context, the use of natural products which, free from side effects, act by counteracting the occurrence of an oral microbiota dysbiosis, protecting from the CDNCDs, could represent a valid adjuvant strategy [21].

Natural bioactive compounds (NBCs) are biological molecules of food origin, mainly contained in plant-based food, which exert important beneficial effects on the human body [22,23]. The NBCs contained in plant-based food are called phytochemicals and they can be classified into different categories, such as polyphenols, carotenoids, alkaloids, phytosterols, nitrogen, and organosulfur compounds [24]. Several in vitro and in vivo studies show that NBCs seem to exert important anti-inflammatory, antioxidant, antimicrobial, anticancer, cardioprotective, neuroprotective, hepatoprotective, hypoglycemia, and anti-hypertensive effects [25-28]. Furthermore, NBCs can positively modulate the oral microbiota composition [18]. Consequently, the intake of NBCs could represent a valid strategy able to counteract the onset and the progression of CDNCDs, including CKD. In this regard, the purpose of this review is to define the relationship between oral diseases and CKD and to analyze the possible role of NBC's consumption in the prevention and treatment of oral diseases. In particular, among the oral diseases, in this review, we examine oral infections, dental and oral bone tissue alterations, saliva and exhaled modifications, and oral soft tissue negative changes.

2. Research Methods

To reach the article purpose, we selected a list of studies according to research online items of"natural bioactive compounds"and "oral disease"and"chronic kidney disease"and"periodontitis"in association with"epigallocatechin gallate"and/or"polyphenols"and/or"oral microbiota"and/or"oral inflammation"and/or"renal replacement therapy"and/or"haemodialysis"and/or"peritoneal dialysis"and/or"kidney transplant" and/or "xerostomia". The databases used were PubMed and Web of Science up to January 2022. Studies were all in the English language and they were manually retrieved by the authors.

3. Oral Health and Chronic Kidney Disease (CKD)

The oral health of CKD patients is significantly compromised, and it is estimated that nearly 90%of them present an oral cavity alteration, including periodontal disease, impaired mineralization of the bone matrix, gingival hyperplasia, and alterations in saliva secretion and composition [29]. Furthermore, CKD patients show a greater predisposition to oral infections[30]. These changes may be related both to CKD itself and to the effect of renal replacement therapy(RRT)[31,32]. At the same time, poor oral hygiene care can favor and exacerbate the chronic low-grade inflammatory state, typical of CKD [33]. To prevent oral diseases in CKD patients, it is necessary to develop specific oral hygiene

strategies. Moreover, it has been shown that the presence of a lesion or other pathological processes of the oral cavity, if not treated, can accelerate the progression or induce the onset of CKD comorbidities [31]. Oral diseases and CKD appear to have a bidirectional correlation with a reciprocal cause-effect relationship (Figure 1) [34].

3.1.Effects of CKD Comorbidities on Oral Health

Some of the main uremic comorbidities may represent important risk factors for the oral alterations onset, including uremic toxins accumulation, normochromic and normocytic anemia, water-electrolyte imbalance, and calcium-phosphorus metabolism alteration, and possible concomitant malnutrition [35].

3.1.1.Saliva and Exhaled Alteration

Nearly one-third of end-stage renal disease (ESRD)patients show a condition known as uremic halitosis [36]. The loss of renal function, especially in more advanced CKD stages, induces urea accumulation both in saliva and serum. In the oral cavity, excess urea is converted into ammonia by the urease-positive microbial flora, responsible for the typical halitosis of ESRD patients [35]. Several studies have shown a direct correlation between the serum accumulation of urea, and other uremic toxins, with the presence of ammonia in CKD patients' exhalation [37]. The ammonia accumulation in the oral cavity is responsible for the reduction in salivary flow and mouth-drying, phenomena usually observed in ESRD patients [36]. Furthermore, this condition leads to the perception of a metallic and unpleasant taste following the ingestion of food, which induces the patient to reduce caloric and protein intake, contributing to the development of protein-energy wasting (PEW) syndrome, typical of CKD patients [38]. CKD patients present often this syndrome which is characterized by muscle hypercatabolism, chronic inflammatory state, and metabolic acidosis [38-40]. This condition causes non-intentional reduction of body weight and loss of muscle mass, with a concomitant increase of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α and interleukin (IL)-6, partly responsible for the onset of a chronic inflammatory state [41. In addition, the pro-inflammatory state tends to decrease the albumin in the circulation, exacerbating the state of malnutrition [42. The establishment and the worsening of PEW syndrome increase the hospitalization rate and all-cause mortality of CKD patients [38]. The loss of muscle mass leads to a further increase in urea levels, in the blood and the saliva, enhancing uremic halitosis and leading to the development of a vicious circle [35]. In addition to serum urea high levels, other factors probably implicated in the onset of uremic halitosis are the increase in the serum phosphorus concentration and the alteration of salivary pH [43-45]. Uremic halitosis can also be associated with a burning sensation on the lips and tongue of neuropathic origin [46] or even with a sensation of an enlarged tongue.

3.1.2. Oral Soft Tissue Alterations

Other oral abnormalities often found in CKD patients concern oral soft tissue. Often CKD patients in more advanced stages present a normochromic and normocytic anemia, mainly due to a deficit in the production of erythropoietin and a reduction in the half-life of red blood cells. The anemia is the basis of the characteristic pallor of the mucous membranes which is often observed in CKD patients [47].

Moreover, a clinical condition known as uremic stomatitis may be encountered in ESRD patients. This is an oral complication of unknown etiology which is relatively uncommon [43,46,48]. Clinically, uremic stomatitis is characterized by the presence of erythematous lesions in the oral cavity, which can be localized or generalized. These lesions are covered with a pseudomembranous exudate that can be removed, leaving an intact or ulcerated mucosa [45]. Uremic stomatitis is determined by lesions that often heal spontaneously, but to promote their healing, the treatment with a mildly acidic rinse, such as 10% hydrogen peroxide, appears to be effective.

3.1.3. Dental Tissue Alterations

In the presence of CKD, it is possible to observe anomalies in the teeth. A sign frequently encountered in CKD patients is enamel hypoplasia. It is mainly associated with the alteration of calcium-phosphorus metabolism [48]. Hypoplasia of the dental enamel is a pathological condition characterized by the lack of development of the dental enamel, which therefore presents a quantitative deficit and a reduced thickness. A patient suffering from enamel hypoplasia experiences problems not only of an aesthetic nature, but this pathological condition can also represent an important risk factor for the development of more serious oral diseases [47]. Dental enamel health is deeply affected by a patient's nutritional status. Vitamin D, calcium, vitamin A deficiency, and the presence of PEW have been associated with enamel hypoplasia, conditions which also lead to increased susceptibility to tooth decay [49]. Enamel hypoplasia is a condition that is often found in CKD pediatric patients. A prolonged deficiency of vitamin A, vitamin D, and calcium during the development of the teeth can lead to enamel atrophy and a dentin defective apposition and calcification |49]. In particular, Bawden et al. hypothesized that a hypovitaminosis D leads to inadequate transport of calcium, useful for the development of the dental tissues [50]. Vitamin D deficiency affects the structure of the teeth, and it delays their physiological eruption. In the presence of vitamin D deficiency, the teeth are microscopically characterized by an extended layer of prevention, the presence of interglobular dentin, and enamel imbalance formation [51]. In CKD adult patients, on the other hand, hypovitaminosis D can lead to the narrowing or the calcification of the pulp chamber [35].

Currently, there is no unambiguous consensus regarding the increased risk of developing dental caries in CKD patients [44]. A potential antibacterial effect was attributed to the increase in salivary pH, due to the hydrolyzation of urea by saliva, suggesting its protective action against caries [47l. In contrast, non-carious tooth loss is more prevalent in CKD patients than in the general population. This loss can be induced by uremic gastritis and by gastro-esophageal reflux, which often occurs in ESRD patients, and can be responsible for tooth erosion [35].

3.1.4. Oral Bone Tissue Alteration

In CKD patients, further alterations of the oral cavity are linked to the alteration of calcium-phosphorus metabolism, vitamin D abnormal metabolism, and compensatory hyperplasia of the parathyroid, causing the development of CKD-mineral and bone disorder (CKD-MBD)[35]. At the oral cavity level, CKD-MBD is characterized by demineralization of the alveolar bone, reduction of trabecular bone, a decrease in cortical bone thickness, metastatic calcifications of soft tissues, fibrocystic lesions, lytic bone areas, fracture of the jaw(spontaneous or after dental procedures), abnormal bone healing after an extraction, and, sometimes, tooth mobility secondary to bone substance loss.

3.2.Effects of Renal Replacement Therapy on Oral Health

In addition to oral changes due to comorbidities related to CKD and CKD itself, other anomalies in the oral cavity can be induced by RRTs, such as dialysis (hemodialysis-HD and peritoneal dialysis) and kidney transplant.

3.2.1.Oral Alteration in Dialysis Patients

In HD patients, the bleeding of the oral mucosa is frequent. It may be due to CKD itself, such as platelet alteration functions and normochromic and normocytic anemia [52,53], or HD treatment. The latter can induce or exacerbate the condition of thrombocytopenia caused by mechanical damage and heparin use during the  HDprocedure. For these reasons, HD predisposes patients to bruising, petechiae, and bleeding in the oral mucosa.

Furthermore, due to the reduced water intake and polypharmacy, a condition of xerostomia is often found in HD and peritoneal dialysis patients [44]. Xerostomia is characterized by dryness of the oral cavity resulting from insufficient salivary secretion or a complete lack of saliva. Based on its pathogenesis, it is classified as true xerostomia (primary xerostomia), resulting from the malfunction of the salivary glands, or pseudo-xerostomia, also known as symptomatic xerostomia(xerostomia spuria), during which the patient has a subjective impression of a dry mouth despite the normal function of the salivary glands [54]. Xerostomia can affect the oral function and can compromise the patient's well-being. Salivary secretions are vital for oral health, as they are involved in mechanical cleaning with a protective function. Hyposalivation can also increase the risk of oral infections, such as candidiasis, and the patient's susceptibility to dental caries, periodontal disease, and tooth loss. In HD patients, epidemiological studies show that oral hygiene is usually poor so the deposits of tartar and plaque can be increased [35]. Currently, few data are present in the literature about the relationship between peritoneal dialysis and CPD.

3.2.2. Oral Alteration in Renal Transplant Patients

Renal transplant patients often undergo immunosuppressive therapy which makes them more susceptible to infections and the development of malignancies [55]. Renal transplant patients are, therefore, more vulnerable to fungal infections, including Candida albicans, which can induce lesions of the oral mucosa and the perioral [35]. One of the main complications of fungal infections is angular cheilitis, which is an inflammatory disorder that affects the corners of the mouth. Angular cheilitis is observed in more than 4% of renal transplant patients. Other forms of candidiasis have been reported in renal transplant patients, including pseudomembranous (1.9%), erythematous (3.8%), and chronic atrophic—also called prosthetic stomatitis (3.8%).

Among viral infections, cytomegalovirus(CMV) and herpes virus simplex(HSV)are frequently associated with the use of immunosuppressive therapy. In particular, the ulceration of the oral mucosa is often associated with CMV infection, with a preference for the lateral edges of the tongue.

In addition, a secondary effect of cyclosporine therapy, known as gingival overgrowth (GO), may be observed in renal transplant patients. GO secondary to immunosuppressive therapy is the most studied oral alteration in renal transplant patients. It has been observed that if patients are treated with a combination of cyclosporine and nifedipine, the prevalence of GO increases to 50%. A study by Marshall et al. highlighted how this effect occurs within 3 months from the beginning of this pharmacological treatment. This overgrowth, which normally begins at the interdental papillae, is most common in the anterior segments of the mouth and on the labial surfaces of the teeth [56]. GO does not seem to have a predilection for the maxilla or the mandible [35]. Given the numerous side effects of cyclosporine affecting the oral cavity, other therapeutic alternatives have been developed. In fact, tacrolimus, rapamycin, and mycophenolate mofetil are used to replace cyclosporine. These therapeutic alternatives are characterized by a GO decrease. However, these drugs are more expensive, and all their side effects are not yet known. For these reasons, in many cases, cyclosporine remains the first immunosuppressive therapeutic option.

Cases of malignant lesions, such as squamous cell carcinoma and Kaposi sarcoma, which could develop in GO areas induced by cyclosporine, have also been described in renal transplant patients. The increased risk of malignant lesions in the oral cavity in renal transplant patients is a direct consequence of long-term immunosuppressive therapy.

3.3. Periodontal Disease and CKD

CPD is an infectious disease caused by Gram-negative bacteria responsible for the destruction of the supporting tissues of the teeth. The presence of these bacteria in the subgingival biofilm causes the release of proteolytic enzymes, capable of degrading the gingival tissue 57l. Periodontal pathogens not only induce inflammation and local destruction of oral tissues but are also associated with the onset of a systemic inflammatory state. An interesting study conducted on 359 CKD patients highlighted how non-surgical periodontal treatment induced a reduction in systemic inflammation, monitored by pro-inflammatory cytokines [58]. Therefore, it is hypothesized that the treatment of CPD in CKD patients may have a positive effect on oxidative stress(OS) and on systemic inflammatory state [16,59]These last represent prognostic factors associated with more sudden worsening of residual renal function [60]. Therefore, it is plausible to hypothesize that CPD may represent an important risk factor for the onset and the progression of CKD58]. Furthermore, the mortality rate of CKD patients seems to be profoundly increased in the presence of periodontitis.

The microbial complexes in the subgingival biofilm during CPD were classified according to their pathogenic potential into five groups: red, green, orange, yellow, and purple [61]. Notably, the red group, which is composed of Tannerella forsythia, Treponema identical, and Porphyromonas gingivalis, has been identified as the major and severe cause of CPD[61]. These phenomena seem to be related to the dysbiosis of the oral microbiota characterized by increased microbial diversity and by the presence of anaerobic bacterial species, highlighting new potential pathogenic species associated with CPD, such as Filifactor alocis, Fretibacterium fastidious and Treponema Vincenti [64,65]. Furthermore, red-complex bacteria and Candida albicans are present more frequently in CKD patients with CPD than in healthy individuals [58]. Therefore, it is essential to perform a periodic examination of the oral cavity in CKD patients to allow an early diagnosis and a prompt treatment of CPD.

Some of these periodontal-pathogenic microorganisms play a direct action in the progression of CKD. In particular, periodontal bacteria can compromise the kidney health through several mechanisms:(i) indirect, such as the systemic bacteremia, which develops from gingival ulcerations and which allows pathogenic microorganisms to enter the bloodstream, and the release of pro-inflammatory cytokines, responsible for tissue destruction;(ii) direct, such as the destruction of the alveolar bone.

During periodontal inflammation, the interaction between the pathogenic microorganism and the immune system leads to the secretion of pro-inflammatory cytokines, which in turn attract other cells of the immune system, more specifically against the recognized pathogen, amplifying the inflammatory state. Cytokines are secreted by different cell groups and can act both as inflammation amplifiers and as responsible for direct tissue destruction. Inflammatory cytokines enhance vascular permeability, which in turn can increase bacteremia and stimulate fibroblasts and inflammatory cells, inducing the release of other cytokines. During inflammation, the expression of endothelial adhesion molecules also increases, such as the intercellular adhesion molecule (ICAM)-1 and the vascular cell adhesion molecule(VCAM)-1, E-selectin and chemokines (monocyte chemoattractant protein-1 andTI8)

Among other typical features associated with CPD, OS plays a pivotal role in the relationship between periodontitis and CKD. In CPD, reactive oxygen species(ROS) are an important primary defense system, and they are produced by inflammatory cells [68]. It is plausible that OS has a significant impact on local periodontal lesions. The effects of OS on systemic inflammation have been demonstrated by several research groups. For example, tissue levels of 8-hydroxydeoxyguanosine (8-OHdG), an OS marker, are increased in multiple organs, such as the liver, heart, kidneys, and brain in an animal model of periodontal inflammation [69]. Therefore, it is hypothesized that the balance between pro-oxidant and antioxidant species is associated with the onset, the severity, and the progression of CPD and its systemic complications [59].