ORAL HEALTH IN PATIENTS WITH CHRONIC KIDNEY DISEASE CORRESPONDENT

1* 2 3 4 Radojica Stolić , Vekoslav Mitrović , Naja Suljković , Dušica V. Miljković-Jakšić , 4 4 4 Aleksandra D. Balović , Roksanda N. Krivčević , Sanja M. Jovanović 1 University of Kragujevac, Serbia, Faculty of Medical Sciences, Department of Internal Medicine, Serbia 2 University of East Sarajevo, Faculty of medicine Foca, Republika Srpska, Bosnia and Herzegovina 3 Health center Novi Pazar, Serbia 4 University of Pristina/Kosovska Mitrovica, Faculty of Medicine, Pristina/K.Mitrovica, Serbia


Actuality of research
Current guidelines in nephrology do not deal with specific problems of oral health in patients with chronic kidney diseases [1]. However, there are several aspects that indirectly affect these problems. In line with the latest evidence of good clinical practice concerning medical and dental referrals for patients on hemodialysis, it will surely become imperative to establish interdisciplinary communication.
During recent years the prevalence of patients with chronic kidney diseases has noticeably increased. For example 14% of the adult population in the United States of America are estimated to suffer from chronic kidney diseases with significant financial costs. In 2008, more than $ 30 billion was spent on their treatment. Patients with moderate kidney diseases were found to have 2-3 times higher mortality than the general population. Namely, chronic kidney diseases is the ninth leading cause of death in the United States of America [2,3].
Almost all chronic diseases are associated with poor oral health, which leads to a need for better dental care. This is particularly evident in patients with chronic kidney diseases, where oral diseases are a potential cause of worsening of their already fragile health. In the global health system dental disease and periodontitis are considered to be among the most expensive conditions to treat [3].
Existing data on the prevalence and severity of oral disease in patients with chronic kidney diseases are limited to a few studies with small samples. They show different incidences of oral disease in such patients. However, based on these meager data it is estimated that nearly 90% of patients with chronic kidney diseases exhibit some symptoms of oral disease, especially gingival enlargement, xerostomia and changes in the flow and composition of saliva [4].
Patients with chronic kidney diseases require special attention in relation to dental services, not only due to conditions typical of this disease, but also because of the multiple oral manifestations, side effects and specificities of therapeutic treatment [4]. The medical, psychological and socio-economic characteristics of individuals with end stage kidney diseases potentially affect oral health problems and contribute not only to quality of life, but also to morbidity and mortality. Up to now, serious studies have documented a link between cardiovascular disease on the one hand, and periodontal disease and gum infections on the other. Current

INTRODUCTION
research indicates a correlation between gum infections and kidney disease. Periodontitis is an inflammatory response to persistent infection caused by bacteria penetrating into the porous gum tissue, and this inflammatory condition can affect major organs, including the kidneys [5].

Search Strategy
In the present article review, scientific articles in the English language published in MEDLINE database.
We used keywords to search the database: Chronic kidney disease, Hemodialysis, Oral health, Periodontal diseases.

Gingival hyperplasia
Gingival hyperplasia, usually a result of drug side effects, is one of the most widely documented oral manifestations in patients with kidney disease. There can also be a so-called additive effect, when hyperplasia mainly affects the labial surface of the interdental papilla [6].
Most epidemiological studies have established paleness of the gingiva (due to the anemia of chronic disease), petechiae and ecchymosis, resulting from anticoagulation therapy and/or platelet dysfunction. Periodontal problems creating large dents and deep pockets often occur in patients with chronic kidney diseases because of these predisposing factors. The prevalence of periodontal disease in this population of patients is increased most likely by immune suppression in uremia. This inhibits the inflammatory response of gingiva to plaque accumulation [5].
Chronic kidney disease and paradontopathy also connect common risk factors, such as diabetes mellitus, [7] age and tobacco smoking [8]. It is believed that periodontal conditions are a non-traditional risk factor for chronic kidney diseases, due to systemic changes caused by periodontal inflammation. Due to the parodontogenic presence of bacteria, inflammatory mediators like interleukin-1, interleukin-6, prostaglandine 2 and tumor necrosis factor alfa are locally produced and their antigens may reach the circulation [9]. Recent studies have shown that, in comparison with healthy people, patients with periodontitis may have elevated levels of C-reactive protein and, consequently, a mild systemic acute phase inflammatory response. Since the connection between chronic systemic infection and chronic kidney diseases, as measured by levels of C-reactive protein, has been long known, periodontitis as a source of "chronic inflammation", may contribute to worsening of the chronic kidney diseases [10]. Xerostomia Xerostomia arises as a result of restricting fluid intake, unwanted effects of drugs (antihypertensives), subsequent to possible lesions of the salivary glands, decreased production of saliva and damage to peripheral airways. Frequent chronic infections of the salivary glands are manifested by raised levels of proinflammatory cytokines in saliva. However, the effect of this increase on oral manifestations has not been extensively studied. Salivary enzymes require an alkaline environment in the oral cavity. The buffering capacity of saliva was found to be significantly reduced in patients with chronic kidney diseases [11,12].

Bad breath and taste in mouth
Patients complain of the sense of an unpleasant odor and metallic taste in the mouth. This is partly due to increased concentrations of salivary urea and its transformation into ammonia [13].

Changes on the oral mucosa
Uremic stomatitis includes lupus, ulcerative and hemorrhagic-hyperkeratotic forms. These lesions are very painful and usually occur on the ventral surface of the tongue, as well as on the front of the mucosal surface, and they are very resistant to treatment but may disappear after 2-3 weeks of intensive dialysis treatment. Mucosal lesions (white plaques and/or ulcerations) appear frequently. Customary findings are lichenoid lesions that are associated with certain drugs and/or oral leukoplakia, as a secondary manifestation of therapy-induced immune suppression. Stomatitis and xerostomia are prevalent among dialysis patients. Stomatitis is characterized by carmine red mucous membranes, while xerostomia arises after rigorous restrictions on liquids and side effects of medicaments. Inadequate treatment of stomatitis and xerostomia can lead to malnutrition because of the impossibility of adequate food intake. In patients on hemodialysis vitamin and mineral deficiencies may occur due to poor appetite, depression, gastrointestinal tract disorders, difficulty in swallowing and dietary restrictions. Vitamin and mineral imbalance can be identified, e.g. lack of vitamin E may cause aphthous stomatitis, but each deficit can be compensated by adequate substitution after completion of dialysis treatment [14][15][16].

Malignity
The most common form of malignancy after kidney transplantation arises due to epithelial dysplasia and cancer of the lips. The increased risk of malignancy in patients with chronic kidney diseases is most likely caused by iatrogenic immunodeficiency, which enhances sensitivity to the mucous-tumor virus, as observed in patients with Kaposi's syndrome and non-Hodgkin's disease [17,18].

Oral infection
Infections, especially candidiasis, are almost a customary finding in patients after kidney transplantation and those on dialysis. Thus, cytomegalovirus infection is common in the first few months after receiving a kidney. Moreover, immunosuppression increases sensitivity to human herpesvirus. Oral infections may lead to increased levels of C-reactive protein, thus raising the incidence of cardiovascular disease [19].

Dental anomalies
Hyperplasia of enamel, due to changes in the metabolism of calcium and phosphorus, can affect both primary and permanent teeth. Its severity depends on the age of patients, the duration of kidney disease and the type of dialysis treatment. Serious erosion of the gingival surface of the teeth may also be observed after frequent vomiting, medication and/or dialysis. Obliteration of the pulp may result from imbalances of calcium and phosphorus metabolism. Loose teeth, malocclusion, calcification of the pulp and temporomandibular joint may also occur. It is interesting that there is a lower prevalence of dental caries. This is attributed to the protective effect of urea, which inhibits bacterial growth and neutralizes bacterial plaques and/or changes the pH of the oral cavity. Changes in dental tissues include: late eruption of teeth, enamel hypoplasia, loss of lamina dura, extension of the periodontal ligament, periodontal destruction, mobility of teeth, dental pulp calcification and narrowing of the pulp chamber [16].

Changes in bone
In patients with chronic kidney diseases mechanisms for physiological regulation of calcium and phosphorus, vitamin D, parathyroid hormone and fibroblast growth factors are marred, which affects the integrity of bone structure leading to renal osteodystrophy. It was found that only 2% of hemodialysis patients have normal values after histomorphometric analysis of bone biopsies. Animal studies indicate a decrease in cortical thickness of the mandible in a mouse model. Changes in bone include: demineralization of the jaw bone, less trabeculation, reduced thickness of cortical bone, metastatic calcification in soft tissues, fibrocystic radiolucent bone lesions, bone fractures and disordered healing after tooth extraction [20][21][22].

The effect of kidney disease on periodontal tissue
The specific effects of kidney disease and kidney replacement therapy on periodontal tissues, include gingival hyperplasia, especially in patients receiving immunosuppressive therapy after kidney transplantation, together with a high level of plaque, calculus, gingival inflammation and increased destruction of the periodontium. Gingival hyperplasia that occurs due to long-term therapy with calcineurin inhibitors and calcium channel blockers, is the most common complication in dialysis patients. Magnification gingiva may be so pronounced that it is often indicated for surgical therapy. Recent studies have shown that the prevalence of cyclosporine-induced gingival hyperplasia in patients with transplants varies between 22 and 58%. Moreover, the addition of a calcium channel blocker, particularly nifedipine, in patients receiving cyclosporine and tacrolimus may raise the frequency and severity of gingival hyperplasia [23][24]. The mechanism of calcineurin inhibitor-induced gingival hyperplasia is not known. However, recent studies have shown that genetic factors are associated with polymorphism of the transforming growth factor beta 1 gene [25].
Studies that focus on the periodontal health of dialysis patients, indicate poor oral hygiene and gingivitis, together with an increased level of dental plaque, calculus and consecutive infections of the gingiva [16,[26][27][28][29][30][31]. This is probably a consequence of the strong uremic syndrome, associated with impaired immune function, as well as altered activity of lymphocytes and monocytes [32]. Many authors have found that the longer is dialysis depuration, the worse is the state of oral health, and this contributes significantly to the num-ber of comorbidities, particularly diabetes mellitus [33].
Periodontitis is associated with elevated values of other components of the acute phase of inflammation, including lower concentrations of high density lipoproteins [34,35], increased amounts of low density lipoproteins [36][37][38] and neutrophils [39]. It is important to note that treatment of pe-riodontal disease can be followed by reduced levels of C-rea-ctive protein [40].
Since diseased periodontal tissue is exposed to chronic inflammation, it is likely that oral bacteria can affect the co-urse of chronic kidney diseases. Greater numbers of perio-dontal red complex bacteria (P. gingivalis, T. forsythia, T. denticola) and C. albicans, as well as significant destruction of periodontal tissue have been found in patients with chro-nic kidney diseases [41] as well as more periodontal bacteria (P. gingivalis, T. forsythia, P. intermedia and P. nigrescens, A. actonomycemconcomitans) in periodontal pockets in these patients [42]. Dialysis patients with severe periodontitis have increased concentrations of proinflammatory cytokines (interleukin-8, tumor necrosis-alfa) and C-reactive protein in the gingival fluid and serum. However, classic nonsurgical treatment of periodontitis can reduce the levels of markers of inflammation [43]. Therefore, regular evaluation and prevention of perio-dontitis is of particular importance in patients with chronic kidney diseases. During periodontitis levels of some pro-inflammatory cytokines (interleukin-1β, interleukin-6, tu-mor necrosis-alfa) increase [39], thereby stimulating the immune system. This modifies the metabolism of fats and enhances production of C-reactive protein, which leads to endothelial dysfunction, a t h e r o s c l e r o s i s , i s c h e m i c h e a r t d i -s e a s e a n d glomerulonephritis [40]. It is therefore not surpri-sing that numerous studies have established a connection be-tween chronic kidney diseases and periodontal disease [44][45][46][47] in patients with end stage kidney disease, most likely due to an altered immune response.

Prevention of oral disease
Prevention of oral disease in patients with chronic kidney diseases involves the application of a series of necessary measures (Table 1) [48].  It is necessary to point out that a nephrologist should be included in the process of providing dental services, and the implementation of adequate measures and procedures in the dental care of hemodialysis patients (Table 2) [48].

CONFLICT OF INTEREST
Comprehensive review of this problem, in patients with terminal renal insufficiency, requires serious cooperation between nephrologists and dentists to make proper communication possible, in order to provide quality dental care for this growing patient population in accordance with new treatment strategies.
The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.