Microinflammation in Renal Failure-Is Periodontal Disease One of the Culprits?: Periodontal Microbiota and Carotid Intima-Media Thickness: The Oral Infections and Vascular Disease Epidemiology Study (INVEST). Circulation 111: 576-582, 2005.

Abstract

There is consensus that microinflammation is common in patients on dialysis (1,2). The evidence for microinflammation consists of increased concentrations of acute phase reactants (3) such as high-sensitivity C reactive protein (hsCRP) (4,5); of cytokines (6), particularly IL-6 (7,8); and of oxidative stress indicators (9,10). Novel markers include fetuin (11) and adiponectin (12,13). Many factors have been suspected or documented to be responsible for microinflammation. They are related to renal replacement therapy (e.g., exposure to proinflammatory stimuli such as bacterial toxins or bacterial DNA in the dialysate, bioincompatibility of dialysis membranes and tubing, etc.) or terminal renal failure (e.g., uremic toxins, advanced glycosylation end (AGE) products, hypervolemia with intestinal leak of endotoxin [14)] etc.). Nevertheless it is of note that increased markers of microinflammation and endothelial cell dysfunction can be found even in nondialysed patients with renal failure early in the course of chronic kidney disease (CKD) (15–17). In that stage of CKD one also finds accelerated atherogenesis (18), possibly triggered by increased oxidative stress (14), providing a link between microinflammation and cardiovascular risk. It is unlikely, however, that one single cause accounts for all microinflammation. In this context it is of interest that a high prevalence of periodontal disease is found in chronic hemodialysis patients (19), particularly in diabetic patients (20). Unpublished preliminary data even suggest that periodontal disease is predicitive of survival (21). Is there a causal link between periodontitis and microinflammation? Following the observations of Ridker and colleagues (22,23) that CRP concentrations predict cardiovascular events, it is of interest to examine whether periodontal disease contributes to the inflammatory burden. Indeed, inflammation markers are found in patients with periodontal disease: Increased hsCRP concentrations, together with reduced flow-mediated vasodilatation of the brachial artery, were noted by Amar et al. (24), although not confirmed by others (25), and higher IL-1β, TNFα, and IL-2 levels are also common (26). After periodontal treatment, white blood cell, neutrophil, and platelet counts decrease significantly (27). Antibodies against and T cells reactive with heat shock protein of Porphyromonas gingivalis were found in the circulation and in atherosclerotic plaques of patients with periodontitis (28). How about cardiovascular risk? A correlation, though modest, was found between periodontal disease and coronary artery calcification as a surrogate marker (29). In the Third National Health and Nutrition Examination Survey (NHANES III), the odds ratio for a heart attack increased with increasing clinical severity of periodontitis (29), and such a relationship was confirmed in the Atherosclerosis Risk in Communities (ARIC) study (30). Sceptics will be impressed by the observation that radical elimination of periodontitis by extraction of all teeth failed to lower cardiovascular risk, however (31). So criticisms had been definitively justified that the available evidence was soft and that more sensitive and comprehensive measures of periodontal disease were required (32). It is the sophisticated methodology used by Desvarieux in the Oral Infection and Vascular Disease Epidemiology Study (INVEST) that now provided more scientifically convincing evidence. Six hundred fifty-seven patients without history of cardiovascular events and with teeth were studied. Subgingival plaque samples were collected and quantitatively assessed by DNA–DNA checkerboard hybridization targeting 11 bacterial species known to be involved in periodontal disease. In addition, the carotid artery intima-media thickness (IMT) was measured and white blood cell counts as well as CRP values were obtained. The main result is that increasing tertiles of overall periodontal bacterial burden, but more importantly increasing tertiles of the burden of causative bacteria (i.e., bacteria involved in plaque formation) were correlated to the carotid IMT. The adjusted IMT values across tertiles of etiologic bacterial burden were 0.84, 0.85, and 0.88—a modest, but statistically significant, increase (P < 0.02). White blood cell counts, but not CRP values, were similarly correlated. The strength of the study is that rigorous molecular bacteriological techniques were used. The weakness is that a surrogate marker (i.e., IMT) but not hard endpoints (i.e., events) were assessed. Nevertheless, the study identifies periodontitis as a definite candidate for, although not yet a convicted culprit in, the genesis of microinflammation and cardiovascular risk. Against the background of the high prevalence of malnutrition, inflammation, and atherosclerosis (MIA syndrome) (1) and of periodontal disease (19,21) in dialysis patients, it is a reasonable hypothesis to propose a link between periodontal disease and microinflammation in these patients. Rigorous studies are currently underway to test this hypothesis. What are the practical consequences? When examining uremic patients it is not medical malpractice but a most sensible procedure to check whether the patient has periodontal disease. And the patient is not hurt by the advice to adopt careful oral hygiene.