Should we aim for oral health to improve outcomes in chronic kidney disease?

Chronic kidney disease (CKD) has well-documented effects on oral tissues including xerostomia, taste disturbance, tongue coating, increased dental calculus and mucosal inflammation [1]. In this issue of NDT Palmer et al. present the largest study to date on oral disease and oral health practices in the setting of CKD stage 5D, the ORALD study [2]. The study has been carried out in more than 4000 haemodialysis patients of European ancestry in 7 countries being treated in selected Diaverum dialysis centres. Most of the patients were examined in Argentina (41%), the other European countries' contributions from Hungary, Italy, France, Poland, Portugal and Spain were more balanced. All patients underwent a full oral examination according to the World Health Organization guidelines for oral health surveys. This approach guarantees the best practice when carrying out a multicentre trial. It was performed by a local dentist trained in periodontitis in each country according to the central study procedures. The mean age of the persons examined was 62 years with about 60% being male and a mean dialysis vintage of 60 months. Diabetes prevalence was 32%, and prior myocardial infarction and stroke were known in 13 and 10% of patients, respectively. Thus the examined population seems to be representative of a typical European haemodialysis cohort. The oral examination found 41% of patients to be affected by moderate to severe periodontitis, with an average of 22 decayed, missing or filled teeth in the dentate population, and 20% of patients to be edentolous. Because edentolous patients can no longer show signs of periodontitis, the proportion of people who are affected by periodontitis increases with decreasing numbers of missing teeth. Compared with a representative German general population sample [3], the proportion of haemodialysis patients who were affected by moderate to severe periodontitis was quite low (41% versus 73% to 88%, depending on age). This might be related to a higher proportion of haemodialysis patients being edentolous and the fact that periodontal disease varied markedly by country. In the present study this was independent of demographics, comorbidity and health practices, with edentulism and periodontitis being least prevalent in Argentina. Predictors of edentulousness were tobacco consumption, diabetes, age and female sex. Moderate to severe periodontitis was independently associated with male sex and serum albumin and, as ‘Karius and Baktus’ taught us, less frequent tooth brushing was predictive of a higher number of decayed, missing and filled teeth. There are several shortcomings that need to be taken into account. First, the study is limited to the short periodontal index that generally overestimates the prevalence of periodontitis. Second, the study is limited to patients of European ancestry. Third, comparing these data in haemodialysis patients with national general population cohorts would have increased the impact of this study further. However, by examining more than 4000 haemodialysis patients in a standardized fashion according to predefined international criteria this study provides the mandatory background information regarding future interventional trials in this field.

Most recent studies on oral disease focus on periodontal health and show intimate associations of gingivitis and periodontitis with the presence of bacterial biofilms adhering to the tooth surfaces. The onset of gingivitis appears to be commonly attributed to insufficient oral hygiene. Thus, the establishment of proper oral hygiene, if necessary supplemented by professional supportive periodontal care, is regarded as the essential standard in the management of this disease. Periodontitis is a bacterially induced, chronic inflammatory disease that affects the tooth-supporting tissues [4]. It is the sixth most common human disease [5]. Periodontitis is characterized by an inflammatory process in the periodontium triggered by the presence of dysbiotic bacterial biofilms accompanied by a bacterial shift to proteolytic, mostly Gram-negative bacterial species [6]. Inflammatory processes are activated and increased production of proinflammatory cytokines leads to pocket formation and bone destruction. Untreated periodontitis may ultimately result in tooth mobility and tooth loss [7]. The severity and progression rate of the disease are also highly dependent on the individual host response towards the presence of bacterial biofilm on the tooth surfaces adjacent to the gingival sulcus [8]. The estimated surface area of this ulcerated epithelium is approximately 40 cm² in severe, untreated periodontitis [9]. Periodontitis results not only in a local, but in a systemic host response. Individuals with periodontitis have elevated systemic markers of acute-phase and oxidative stress response [10]. Systemic inflammation is recognized as a non-traditional risk factor associated with increased risk of CKD progression [11] and cardiovascular events in non-dialysed and dialysed CKD patients [12, 13]. Cardiovascular disease, so far, is one major area in periodontal research [14]. Several meta-analyses have concluded that the available evidence displays a positive association of periodontitis with cardiovascular disease [15] and other disease processes such as diabetes and metabolic syndrome [16, 17]. Cardiovascular disease is the main cause of mortality in CKD [18]. In patients with CKD stages 3–5 periodontitis is associated with all-cause mortality [19] and in nationally representative cross-sectional surveys, there is increasing evidence of associations between CKD and periodontal disease, with a higher proportion of those with CKD having periodontal disease and vice versa [20]. Finally, periodontal disease has emerged as a non-traditional risk factor for CKD [21, 22].

These epidemiological findings are further strengthened by experimental data linking periodontitis and atherosclerotic disease. The entry of oral bacteria and bacterial products into the circulation might be a key initiator with DNA from oral bacteria being isolated from atherosclerotic specimens [23] and bacteraemia being invariably associated with chronic periodontitis [24]. The incidence and magnitude of bactaeremia correlates with the periodontal status [24]. Virulence factors such as Trypsin-like cysteine proteinases, leukotoxins and fimbriae are the central focus of mechanistic studies [25]. In animal models accelerated atherosclerosis was induced by intravenous injection with the oral pathogen Porphyromonas gingivalis [26]. Periodontitis shows a promoting effect on lipid metabolism with periodontal disease resulting in an increase of plasma cholesterol [27] and may further diminish the anti-atherogenic potential of high-density lipoproteins.

The question now is whether vice versa, the treatment of periodontal disease may improve outcome distant from the oral cavity. The standard anti-infective periodontal therapy consists of a full-mouth scaling (sub- and supragingival debridement) followed by an adjunctive systemic antibiotic therapy where needed and an after-care treatment consisting of renewed supra- and subgingival debridement. Increasing evidence shows that periodontal therapy, including oral hygiene instructions, scaling and root planning, results in a reduction of the inflammatory burden by a decrease in serum levels of C-reactive protein and interleukin-6, depending on the intensity and duration of the therapy applied [10, 28]. Accordingly, endothelial dysfunction, considered to be the initial inflammatory alteration leading to atherosclerosis, was improved after intensive periodontal treatment in patients with severe periodontitis [29]. Similar data are available regarding the intima media thickness (IMT). Whereas subjects with severe generalized periodontitis showed a higher risk of having IMT of 1 mm or more, treatment of generalized periodontitis was associated with a significant decrease of IMT [30]. Finally, the question arises of whether the progression of CKD and the incidence of cardiovascular events can be reduced by periodontal therapy.

Up to now, the effect of periodontal treatment on kidney function has been investigated by a few, small studies. In a prospective cohort investigating 20 healthy people, it was reported that successful periodontal treatment improved cystatin C levels but had no effect on estimated glomerular filtration rate (eGFR) after 3 months (mean change −1.4 mL/min/1.73 m²) [31]. In a non-randomized clinical trial involving 40 people, periodontal therapy significantly improved eGFR among patients with CKD (mean change 4.2 mL/min/1.73 m²), whereas there were no differences in serum creatinine [32]. Among 11 children with immunoglobulin A nephropathy, a reduction in proteinuria was obtained following an extensive treatment of infectious foci, including periodontal therapy, tonsillectomy, methylprednisolone pulse therapy and angiotensin II receptor blockade [33]. There are substantial shortcomings with each of these studies including small sample sizes, only one periodontal therapy session and no randomized controlled design. Two randomized controlled studies of periodontal interventions in patients with CKD have been performed and were limited to cohorts of haemodialysis patients. These have generated conflicting results either not indicating changes in inflammatory markers [34] or demonstrating that significant reductions in inflammatory markers can be achieved following periodontal therapy [35].

However, the overall evidence suggests that periodontal health may improve cardiovascular and renal outcomes, and a more robust, clear-cut, clinical trial study design is needed to prove this hypothesis. Up to now, studies on oral health in CKD patients have been small, used non-standardized methods to evaluate oral disease and provided heterogeneous results. This has prevented the calculation of stable estimates of oral disease prevalence and risk factors that are a prerequisite for planning strategies to improve oral health. Now, the ORALD study provides a reliable basis for future interventional trials by giving a detailed description of the oral health status in a large, representative haemodialysis cohort using standardized international methods. Furthermore, it demonstrated the feasibility of a large scale study in this field. Thus, the first major step in the direction of an interventional trial has been taken by performing the ORALD study and a first randomized interventional trial is following this way [36]. In order to improve outcomes, patients with CKD are currently managed to strict targets regarding blood pressure, glycaemic control, lipid lowering therapy and smoking cessation. Demonstration of a significant attenuation of CKD and cardiovascular disease progression by treatment of periodontitis has the potential to introduce an important, new and widely available treatment strategy for improving clinical outcome in CKD patients.

CONFLICT OF INTEREST STATEMENT

None declared. (See related article by Palmer et al. Patterns of oral disease in adults with chronic kidney disease treated with hemodialysis. Nephrol Dial Transplant 2016; 31: 1647–1653)

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