Volume 81 Number 5

Periodontitis and Inammatory Markers in Transplant Recipients

Murad Shaqman,* Efe Ioannidou,* Joseph Burleson, David Hull, and Anna Dongari-Bagtzoglou*
Background: Inammation is associated with the deterioration of solid-organ transplants. Chronic periodontitis is linked to systemic inammation, although it is unknown whether it plays a causative or comorbid role. We hypothesized that transplant subjects have a greater prevalence of severe periodontitis, accompanied by higher levels of serum interleukin-6 (IL-6) and C-reactive protein (CRP), compared to systemically healthy subjects. Methods: We recruited 90 renal and cardiac transplant recipients and 72 age-matched controls and compared their periodontal and systemic inammatory status. Results: The prevalence of severe periodontitis was not statistically signicantly different between transplant and control subjects. Serum IL-6 and CRP were higher in transplant subjects compared to control subjects and in subjects with severe periodontitis compared to subjects without periodontitis, but multivariate analysis showed that severe periodontitis was a signicant positive predictor of serum IL-6 in the control group only. In the test group, signicant predictors of systemic inammation were age, diabetes, higher body mass index, and a cadaveric transplant donor. Conclusion: Despite the presence of higher levels of systemic markers of inammation in transplant subjects with severe periodontitis compared to transplant subjects without periodontitis, periodontal parameters were not statistical predictors of systemic inammation in this population in a multivariate model. J Periodontol 2010;81:666-672. KEY WORDS C-reactive protein; chronic periodontitis; inammation; interleukin-6; organ transplant.
* Department of Oral Health and Diagnostic Sciences, Division of Periodontology, School of Dental Medicine, University of Connecticut Health Center, Farmington, CT. Department of Community Medicine and Health Care, School of Medicine, University of Connecticut Health Center. Transplant Unit, Hartford Hospital, Hartford, CT.

he link between periodontal inammation and systemic health has been the focus of much scientic research in the past few years.1-3 This was stimulated by a better understanding of the role of inammation in the pathogenesis of periodontitis and certain systemic diseases.1-3 One proposed pathogenetic mechanism is that the excessive release of inammatory cytokines in diseased periodontal tissues contributes to the serum cytokine pool, which promotes systemic disease. Evidence supporting this hypothesis comes from ex vivo and clinical studies.4-6 Cells within the diseased periodontium produce signicantly higher levels of interleukin-6 (IL-6) compared to healthy gingival tissues, and periodontal disease was linked to higher serum IL-6 in studies.4,5 Similarly, serum C-reactive protein (CRP) was reported to be elevated in patients with periodontitis.6 Perhaps the most convincing evidence for a causal association between systemic and periodontal inammation comes from studies showing that the treatment of periodontitis reduced serum glycated hemoglobin and inammatory marker levels in subjects with diabetes7 and in systemically healthy subjects.8 Solid-organ transplantation is the denitive therapeutic approach in patients with end-stage organ disease. The kidney and heart are the most commonly transplanted organs, with more than 17,000 kidney and 2,000 heart transplants performed in the United States in 2008.9 Despite the high graft survival
doi: 10.1902/jop.2010.090570

666

J Periodontol May 2010

Shaqman, Ioannidou, Burleson, Hull, Dongari-Bagtzoglou

rates after the rst year post-transplantation (>85%), the 10-year graft survival rates decreased dramatically (<55%).9 The main pathogenetic mechanism for the deterioration of chronic transplants is inammation, which is modulated by alloimmune-dependent (human leukocyte antigen [HLA] mismatches, panel reactive antibody [PRA] scores, and acute rejection) and alloimmune-independent factors (cold ischemic time, ischemia/reperfusion injury, smoking, diabetes, and living versus cadaveric donors).10,11 Clinically, serum and urine IL-6 levels are indicators of acute rejection episodes,12,13 and successful antirejection therapy reduces serum IL-6.14 Similarly, CRP was shown to be a predictor of renal allograft survival.15 Given the importance of IL-6 and CRP in transplant deterioration and the link between periodontitis and these systemic inammatory markers, we explored whether periodontitis may be a modier of systemic IL-6 and CRP in solid-organ transplant recipients. Thus, the goals of this study are: 1) to assess the periodontal statuses of organ-transplant recipients and compare them to an age-matched healthy group, and 2) to compare serum IL-6 and CRP levels in subjects with and without periodontitis in both groups. MATERIALS AND METHODS Study Design and Subject Recruitment We conducted a cross-sectional study from December 2003 to September 2006 to evaluate the association between the periodontal and systemic inammatory statuses of 144 organ-transplant recipients. The primary outcome of the study was a prevalence of severe periodontitis. The secondary outcomes were serum IL6 and CRP levels. Severe periodontitis was dened using the Center for Disease Control/American Academy of Periodontology (CDC/AAP) denition criteria, i.e., the presence of 2 interproximal sites with clinical attachment level (CAL) 6 mm and one interproximal site with a probing depth (PD) 5 mm.16 The study was approved by the Institutional Review Boards (IRBs) of the University of Connecticut Health Center (UCHC) and Hartford Hospital. A total of 144 renal and cardiac transplant recipients were screened during routine outpatient visits at the Hartford Hospital Transplant Center. For inclusion into the study, subjects had to: 1) be clinically stable (measured by serum creatinine levels and a cardiac ejection fraction in renal and cardiac transplant patients, respectively); 2) be at least 1 year post-transplant; 3) have an absence of other systemic conditions that might directly affect systemic inammatory status, e.g., rheumatoid or autoimmune diseases; 4) have a negative history of acute infections and antibiotic use during the preceding 4 months; and 5) have had no periodontal treatment within the previous year. Ninety renal and

cardiac transplant patients met these criteria and signed the IRB-approved informed consent forms. The strategy for recruitment of controls included: 1) an e-mail to UCHC employees, 2) invitation letters mailed to patients in the General Clinical Research Center and Womens Health Center at UCHC, and 3) advertisements in local newspapers. Seventy-two systemically healthy subjects with no history of periodontal treatment within the previous year and no history of antibiotic use during the preceding 4 months were recruited (36 UCHC employees, 16 respondents to the invitation letter, and 20 respondents to the newspaper advertisement). The two groups were matched with respect to age and smoking status. Medical Data Hospital records were reviewed, and data were collected, using a standardized form that included demographic information (age, gender, and ethnicity) and medical information such as weight, height, diabetes (yes/no), smoking history, post-transplant years, history of rejection episodes, medication regimen/dosages, HLA mismatching, PRA score, and donor type (cadaveric versus living and related versus unrelated). The body mass index (BMI) was calculated as weight in kilograms divided by the square of height in meters. Diabetes was used as a categoric variable with a threshold of fasting blood glucose levels >126 mg/dl. A detailed self-reported medical history was used in the control group. Periodontal Examination A periodontal examination was performed by four periodontists (EI, ADB, DK, NC) who were calibrated before the initiation of the study. All subjects received a comprehensive oral examination including the number of missing teeth excluding third molars, plaque score (PS), bleeding on probing (BOP), PD, CAL, and gingival overgrowth (GO).17 Laboratory Assessments Fifteen milliliters of venous blood was drawn from all subjects before the oral examination. Within 2 hours of blood collection, sera were separated after clotting for 30 minutes at 4C, followed by centrifugation at 3,000 g for 15 minutes. Aliquots were stored at -80C until testing. Sera were coded and analyzed in duplicate by enzyme-linked immunosorbent assay. The analytic sensitivities of the IL-6 and CRP assays were 2.0 pg/ml and <0.3 mg/l, respectively, and the variation in protein values within runs was <1% for both assays. Statistical Analyses Means and medians of continuous periodontal variables and percentage of sites with PD 5 mm or
Diagnostic Products, Los Angeles, CA.

667

Periodontitis and Inammation in Transplant Recipients

Volume 81 Number 5

CAL 4 mm were calculated for each subject and group. Considering the frequency distribution of the values above the threshold of detection, undetectable serum IL-6 values were recorded as 0.5 pg/ml. Natural logarithm transformation was applied to non-normally distributed variables. Continuous and dichotomous variables were compared between groups using a two-sample Student t test or x2 test, respectively. Multivariate linear regression analysis determined predictors of serum IL-6 and CRP. Our sample size permitted the detection of an effect size of 0.18 at P = 0.05 in a multivariate analysis with six predictors and b 0.2. The Pearson correlation was used to test associations among serum IL-6, CRP, and continuous periodontal variables. RESULTS Population Characteristics and Periodontal Findings Population demographics and periodontal and serum ndings in transplant and control groups appear in Tables 1 and 2. Compared to the transplant group, the control group had slightly more females, lower BMI, and a lower percentage of individuals with diabetes. The mean PD, percentage of sites with PD

5 mm, percentage of sites with CAL 4 mm, and the number of missing teeth were higher in the transplant group compared to the control group. Twentyone percent of the transplant subjects had severe chronic periodontitis compared to 15% of the control subjects, but the difference was not statistically significant (P = 0.34). A total of 6.5% of the transplant group had mild localized GO (score 1) compared to 0% in the control group. The PS was similar in both groups. However, the control group had higher mean BOP, with a trend toward signicance (P = 0.06), compared to the transplant group. In both groups, there were no current smokers. Serum IL-6, CRP, and Periodontal Status The transplant group had a higher mean serum IL-6 and CRP compared to the control group (Table 1). Serum IL-6 and CRP levels were positively correlated with each other in the transplant group (r = 0.46; P <0.001) and the control group (r = 0.35; P = 0.003). In the transplant group, there was no signicant correlation between serum IL-6 or CRP levels and any of the periodontal indices, but the number of missing teeth showed a positive correlation with serum IL-6 (r = 0.29; P = 0.006).

Table 1.

Characteristics of Transplant and Control Groups

Transplant Group (n = 90) Variable Age (years) Gender (female) (%) Diabetes (%) BMI PD (mm) CAL (mm) BOP (%) PS (%) Missing teeth (n) Sites with CAL 4 mm (%) Sites with PD 5 mm (%) Severe periodontitis (%) IL-6 (pg/ml) CRP (mg/l)
NS = not signicant. 2 * t or x test.

Control Group (n = 72) Mean SD 51 12 60 3 Median (quartiles) 51 (43, 59) P* 0.33 (NS) 0.027 <0.001 26.2 (24.0, 30.6) 2.4 (2.2, 2.7) 2.6 (2.3, 3.0) 17.0 (8.7, 34.0) 53.3 (22.9, 73.5) 1 (0, 3) 3.8 (0.0, 14.3) 0.0 (0.0, 2.6) 0.007 0.001 0.06 (NS) 0.06 (NS) 0.60 (NS) <0.001 0.046 0.013 0.34 2.5 (2.0, 3.7) 0.12 (0.05, 0.28) <0.000 <0.000

Mean SD 53 12 42 56 30.2 7.2 2.7 0.5 2.9 0.7 17.0 16.7 46.6 30.0 4.2 4.9 14.4 16.9 5.2 7.9 21 5.0 4.3 0.9 1.63

Median (quartiles) 53.5 (44, 61)

29.3 (24.5, 33.5) 2.6 (2.4, 3.0) 2.8 (2.5, 3.2) 11.9 (4.8, 22.5) 45.9 (19.1, 71.7) 3 (1, 6) 8.7 (2.8, 18.7) 1.3 (0.0, 8.3)

27.3 5.0 2.4 0.4 2.7 0.6 22.0 16.7 49.0 28.5 1.7 2.2 9.6 13.5 2.6 5.2 15

3.3 (2.4, 5.1) 0.30 (0.10, 0.82)

3.0 1.6 0.28 0.39

668

J Periodontol May 2010

Shaqman, Ioannidou, Burleson, Hull, Dongari-Bagtzoglou

Table 2.

Medical and Demographic Data of the Transplant Population

Variable Transplant type (kidney) (% frequency) Ethnicity (black) (% frequency) Post-transplant years (mean SD; median [quartiles]) History of acute rejection (% frequency) Pretransplant dialysis (% frequency) Living donor (related or unrelated) (% frequency) Cyclosporine (% frequency) GO (% frequency) Ca++ channel blockers (% frequency) Prednisone (% frequency) Mycophenolate (% frequency) Tacrolimus (% frequency) Azathioprine (% frequency) Sirolimus (% frequency) Transplant Subjects (n = 90) 90 32 6.9 4.8; 5.0 (3.0, 10.0) 36 68 42 24 6.5 29 87 72 54 10 7

Predictors of Serum Inammatory Markers In the transplant group, independent predictors of serum markers that were tested in the multivariate model were age, gender, diabetes (yes/no), BMI, posttransplant years, immunosuppressant dose (prednisone, dichotomized at the 75 percentile), cyclosporine (yes/no), tacrolimus (yes/no), history of rejection (yes/no), living donor (yes/no), HLA mismatches, PRA score, severe periodontitis, and all continuous periodontal variables. Variables with P >0.2 were excluded from the model. The nal model is shown in Tables 3 and 4. Signicant predictors of higher serum IL-6 in the transplant group were age, diabetes, higher BMI, and cadaveric donor, whereas the number of post-transplant years approached statistical signicance. In the control group, severe periodontitis, higher BOP, and a greater percentage of sites with PD 5 mm were signicant predictors of higher serum IL-6, whereas the BMI approached statistical signicance (Table 3). With respect to serum CRP levels, diabetes and a higher BMI were signicant predictors of higher CRP in the transplant group, whereas only a higher BMI was a signicant predictor in the control group (Table 4). DISCUSSION The prevalence of severe chronic periodontitis in our transplant population was not signicantly higher than in the control group. The signicant differences we observed in certain continuous periodontal variables were not unexpected considering that the transplant group had a greater prevalence of diabetes, which is a risk factor for periodontitis.18,19 Other studies reported a higher,20,21 similar,22 or lower23 prevalence of periodontitis in transplant subjects compared to controls. However, differences in periodontitis case denitions prohibited a direct comparison among studies. In the present study, periodontitis was dened using the CDC/AAP criteria for severe periodontitis.16 This denition was chosen for several reasons. First, the denition is very stringent in its severe disease category, so that true disease can be detected outside the margin of measurement error. Second, this classication enables the identication of a population subset with a more pronounced and more readily identiable systemic impact of periodontal inammation.24,25 Third, the adoption of this denition in our study and, hopefully, in future population-based studies will make the interpretation and comparison of data feasible and more benecial. The transplanted organ constitutes a constant challenge to the host immune system. The chronic low-grade activation of inammatory cells results in a cascade of events leading to elevated systemic
669

Despite the lack of correlation among serum IL-6 and periodontal parameters, transplant patients with severe periodontitis had a signicantly higher serum IL-6 compared to transplant subjects without periodontitis (6.0 4.2 pg/ml versus 4.7 4.4 pg/ml; P = 0.04), and there was also a trend toward higher serum CRP levels in transplant patients with severe periodontitis compared to transplant subjects without periodontitis (1.36 1.89 mg/l versus 0.77 1.54 mg/l, respectively; P = 0.12). In the control group, serum IL-6 levels were positively correlated with the mean PD (r = 0.37; P = 0.002), percentage of sites with PD 5 mm (r = 0.33; P = 0.006), and mean BOP (r = 0.38; P = 0.001). Similarly, in the control group, serum CRP levels were positively correlated with mean PD (r = 0.30; P = 0.01) and CAL (r = 0.29; P = 0.01), whereas the correlation with the percentage of sites with PD 5 mm approached statistical signicance (r = 0.23; P = 0.06). Differences in serum markers between control subjects with severe periodontitis and control subjects without periodontitis did not reach statistical signicance (3.7 1.3 pg/ml versus 2.9 1.6 pg/ml [P = 0.06] and 0.38 0.42 versus 0.27 0.38 [P = 0.38] for IL-6 and CRP, respectively).

Periodontitis and Inammation in Transplant Recipients

Volume 81 Number 5

Table 3.

Multivariate Linear Regression Analysis With Serum IL-6 as the Dependent Variable
Variable Transplant group* Age Diabetes BMI Cadaveric donor Number of post-transplant years Number of missing teeth Control group Gender Age Diabetes BMI Severe periodontitis Percentage of sites with BOP
* r2 = 0.30. 2 r = 0.26.

F 7.93 6.30 7.10 6.21 3.00 3.52 0.002 0.42 0.20 3.56 6.51 10.40

P <0.01 <0.02 <0.01 <0.02 0.09 0.06 0.96 0.52 0.66 0.06 0.01 <0.01

b 0.30 0.27 0.29 0.27 0.19 0.21 <0.01 0.08 0.05 0.24 0.31 0.39

Table 4.

Multivariate Linear Regression Analysis With Serum CRP as the Dependent Variable
Variable Transplant group* Age Diabetes BMI Severe periodontitis Control group Age Diabetes BMI Severe periodontitis
* r2 = 0.23. 2 r = 0.21.

F 2.31 8.48 11.66 1.56 0.98 0.81 14.23 0.09

P 0.13 0.005 0.001 0.22 0.33 0.37 <0.001 0.76

b 0.16 0.30 0.35 0.14 0.13 0.11 0.43 0.04

was not a signicant predictor in the transplant group (F = 0.06; P = 0.8). Signicant predictors of systemic inammation in our regression models in transplant subjects were age, diabetes, higher BMI, and a cadaveric donor, which were consistent with other articles.33-36 Obesity as expressed by BMI levels 30 kg/m2 was linked to a low-grade inammation with elevated levels of serum CRP, tumor necrosis factor-a, and IL-6 in other populations.37 Moreover, pretransplant diabetes and new-onset diabetes after transplantation were associated with higher levels of inammation and oxidative stress.38 Furthermore, the age of the donor and recipient is an established predictor of posttransplant outcome based on a prediction model by Ghobrial et al.39 The lack of signicance in the multivariate analysis between periodontal parameters and inammatory markers in transplant subjects, which contradicts some of the preliminary ndings of Ioannidou et al.,29 could be due to several reasons. A possible explanation is a true lack of association, given the strong inammatory confounding by diabetes and the constant allograft-mediated antigenic stimulation in transplant subjects. Another reason could be that periodontally driven inammation is dampened by immunosuppressive therapy, which is supported by the nding that transplant patients experience limited progression of periodontitis after the initiation of immunosuppression22 and reduced gingival inammation (as expressed by mean BOP levels) compared to control subjects, as shown in the present study. CONCLUSIONS The cross-sectional nature of this study prevented the assessment of a cause-and-effect relationship between periodontitis and systemic inammation. Future research should aim at a longitudinal evaluation of periodontal indexes and their correlation with systemic markers of inammation as well as the inuence of periodontal treatment on local and systemic markers of inammation in this population. ACKNOWLEDGMENTS This study was supported by the National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland (grant R21DE16466 to Dr. Dongari-Bagtzoglou). This research was also supported, in part, by a General Clinical Research Center grant (M01RR06192) awarded to UCHC from the National Institutes of Health. The authors would like to thank Drs. Nancy Chang and David Kao for their valuable participation as periodontal examiners in the study. The authors report no conicts of interest related to this study.

inammatory mediator levels.26,27 This explains our nding of elevated levels in circulating IL-6 and CRP in transplant subjects compared to healthy controls, as was shown in previous articles by Cottone et al.28 and Ioannidou et al.29 The observed positive association between serum IL-6 and CRP levels was expected because IL-6 triggers CRP synthesis by the liver.30 Interestingly, studies31,32 reported that the exact sources of serum IL-6 are unclear and may originate in tissues other than the transplanted organ. Although severe periodontitis was a signicant predictor of serum IL-6 in the control group in the present study, it
670

J Periodontol May 2010

Shaqman, Ioannidou, Burleson, Hull, Dongari-Bagtzoglou

REFERENCES
1. Ross R. Atherosclerosis An inammatory disease. N Engl J Med 1999;340:115-126. 2. Kinane DF, Lappin DF. Immune processes in periodontal disease: A review. Ann Periodontol 2002;7: 62-71. 3. Shoelson SE, Lee J, Goldne AB. Inammation and insulin resistance. J Clin Invest 2006;116:1793-1801. (erratum 2006;116:2308). 4. Dongari-Bagtzoglou AI, Ebersole JL. Increased presence of interleukin-6 (IL-6) and IL-8 secreting broblast subpopulations in adult periodontitis. J Periodontol 1998;69:899-910. 5. Takahashi K, Takashiba S, Nagai A, et al. Assessment of interleukin-6 in the pathogenesis of periodontal disease. J Periodontol 1994;65:147-153. 6. Paraskevas S, Huizinga JD, Loos BG. A systematic review and meta-analyses on C-reactive protein in relation to periodontitis. J Clin Periodontol 2008;35: 277-290. 7. OConnell PA, Taba M, Nomizo A, et al. Effects of periodontal therapy on glycemic control and inammatory markers. J Periodontol 2008;79:774-783. 8. Tonetti MS, DAiuto F, Nibali L, et al. Treatment of periodontitis and endothelial function. N Engl J Med 2007;356:911-920. 9. Health Resources and Services Administration. 2007 Annual Report of the U.S. Organ Procurement and Transplantation Network and the Scientic Registry of Transplant Recipients: Transplant Data 1997-2006. Rockville, MD: U.S. Department of Health and Human Services; 2007. 10. Yates PJ, Nicholson ML. The aetiology and pathogenesis of chronic allograft nephropathy. Transpl Immunol 2006;16:148-157. 11. Ramzy D, Rao V, Brahm J, Miriuka S, Delgado D, Ross HJ. Cardiac allograft vasculopathy: A review. Can J Surg 2005;48:319-327. 12. Hartono C, Dadhania D, Suthanthiran M. Noninvasive diagnosis of acute rejection of solid organ transplants. Front Biosci 2004;9:145-153. 13. Raasveld MH, Bloemena E, Wilmink JM, Surachno S, Schellekens PT, ten Berge RJ. Interleukin-6 and neopterin in renal transplant recipients: A longitudinal study. Transpl Int 1993;6:89-94. 14. Van Oers MH, Van der Heyden AA, Aarden LA. Interleukin 6 (IL-6) in serum and urine of renal transplant recipients. Clin Exp Immunol 1988;71: 314-319. 15. van Ree RM, Oterdoom LH, de Vries AP, et al. Elevated levels of C-reactive protein independently predict accelerated deterioration of graft function in renal transplant recipients. Nephrol Dial Transplant 2007; 22:246-253. 16. Page RC, Eke PI. Case denitions for use in population-based surveillance of periodontitis. J Periodontol 2007;78(Suppl. 7):1387-1399. 17. Pernu HE, Pernu LM, Huttunen KR, Nieminen PA, Knuuttila ML. Gingival overgrowth among renal transplant recipients related to immunosuppressive medication and possible local background factors. J Periodontol 1992;63:548-553. 18. Papapanou PN. Periodontal diseases: Epidemiology. Ann Periodontol 1996;1:1-36. 19. Tomar SL, Asma S. Smoking-attributable periodontitis in the United States: Findings from NHANES III. 20. 21.

22. 23.

24.

25.

26. 27. 28.

29.

30. 31. 32.

33.

34.

35.

36.

National Health and Nutrition Examination Survey. J Periodontol 2000;71:743-751. Leung WK, Yau JY, Jin LJ, et al. Subgingival microbiota of renal transplant recipients. Oral Microbiol Immunol 2003;18:37-44. Lessem J, Drisko C, Greenwell H, et al. Are cardiac transplant patients more likely to have periodontitis? A case record study. J Int Acad Periodontol 2002;4: 95-100. Oshrain HI, Telsey B, Mandel ID. A longitudinal study of periodontal disease in patients with reduced immunocapacity. J Periodontol 1983;54:151-154. Rahman MM, Caglayan F, Rahman B. Periodontal health parameters in patients with chronic renal failure and renal transplants receiving immunosuppressive therapy. J Nihon Univ Sch Dent 1992;34: 265-272. DAiuto F, Nibali L, Parkar M, Suvan J, Tonetti MS. Short-term effects of intensive periodontal therapy on serum inammatory markers and cholesterol. J Dent Res 2005;84:269-273. Noack B, Genco RJ, Trevisan M, Grossi S, Zambon JJ, De Nardin E. Periodontal infections contribute to elevated systemic C-reactive protein level. J Periodontol 2001;72:1221-1227. Allan JS, Madsen JC. Recent advances in the immunology of chronic rejection. Curr Opin Nephrol Hypertens 2002;11:315-321. Nocera A, Tagliamacco A, De Palma R, et al. Cytokine mRNA expression in chronically rejected human renal allografts. Clin Transplant 2004;18:564-570. Cottone S, Palermo A, Vaccaro F, et al. In renal transplanted patients inammation and oxidative stress are interrelated. Transplant Proc 2006;38: 1026-1030. Ioannidou E, Kao D, Chang N, Burleson J, DongariBagtzoglou A. Elevated serum interleukin-6 (IL-6) in solid-organ transplant recipients is positively associated with tissue destruction and IL-6 gene expression in the periodontium. J Periodontol 2006;77:18711878. Van Snick J. Interleukin-6: An overview. Annu Rev Immunol 1990;8:253-278. Cainelli F, Vento S. Infections and solid organ transplant rejection: A cause-and-effect relationship? Lancet Infect Dis 2002;2:539-549. rfer M, Riess Waiser J, Budde K, Katalinic A, Kuerzdo R, Neumayer HH. Interleukin-6 expression after renal transplantation. Nephrol Dial Transplant 1997;12: 753-759. Papanicolaou DA, Wilder RL, Manolagas SC, Chrousos GP. The pathophysiologic roles of interleukin-6 in human disease. Ann Intern Med 1998;128: 127-137. Panagiotakos DB, Pitsavos C, Yannakoulia M, Chrysohoou C, Stefanadis C. The implication of obesity and central fat on markers of chronic inammation: The ATTICA study. Atherosclerosis 2005;183: 308-315. Herder C, Schneitler S, Rathmann W, et al. Low-grade inammation, obesity, and insulin resistance in adolescents. J Clin Endocrinol Metab 2007;92:45694574. Pickup JC. Inammation and activated innate immunity in the pathogenesis of type 2 diabetes. Diabetes Care 2004;27:813-823. 671

Periodontitis and Inammation in Transplant Recipients

Volume 81 Number 5

37. Bastard JP, Maachi M, Lagathu C, et al. Recent advances in the relationship between obesity, inammation, and insulin resistance. Eur Cytokine Netw 2006;17:4-12. 38. Morales-Indiano C, Lauzurica R, Pastor MC, et al. Greater posttransplant inammation and oxidation are associated with worsening kidney function in patients with pretransplant diabetes mellitus. Transplant Proc 2009;41:2126-2128. 39. Ghobrial RM, Gornbein J, Steadman R, et al. Pretransplant model to predict posttransplant survival in liver

transplant patients. Ann Surg 2002;236:315-322; discussion 322-313. Correspondence: Dr. Anna Dongari-Bagtzoglou, Division of Periodontology, University of Connecticut Health Center, 253 Farmington Ave., Farmington, CT 06030-1710. E-mail: adongari@uchc.edu. Submitted October 8, 2009; accepted for publication December 22, 2009.

672