Commentary Periodontitis and Chronic Kidney Disease Frank A. Scannapieco* and Mandip Panesar † S ince the late 1980s, there has been a growing literature that suggests that periodontal dis- eases may contribute to a variety of significant acute and chronic systemic diseases. Although the connections between periodontal disease and athero- sclerosis, heart disease, and stroke have been well publicized, other potentially significant connections have been made with diabetes, obstetric complica- tions, respiratory disease, Alzheimer’s disease, and other diseases. 1 A biologically plausible common link between periodontal diseases and many systemic diseases appears to be infection and inflammation. This issue of the Journal of Periodontology presents an article that makes the case for a connection be- tween periodontal diseases and chronic kidney disease (CKD). 1 CKD is a catchall term for a variety of chronic con- ditions that result in compromised kidney function, which is measured as the glomerular filtration rate (GFR). The gold standard to determine the GFR in patients is to measure the clearance of insulin since it is not secreted by the renal tubules, but this remains an im- practical test to perform clinically. Therefore, clini- cians have relied on the measurement of serum creatinine as an indirect measure of the GFR and use creatinine-based formulae to calculate the GFR. There is a high degree of physiologic variability in GFR among normal individuals, thus making it diffi- cult to define limits for normal GFR. The guidelines de- veloped by the National Kidney Foundation’s Kidney Disease and Outcomes Quality Initiative (K/DOQI) 3 have defined five stages of CKD on the basis of differ- ent ranges of GFR: stage 1 GFR >90 ml/minute/1.73 m 2 , stage 2 GFR 60 to 89 ml/minute/1.73 m 2 , stage 3 GFR 30 to 59 ml/minute/1.73 m 2 , stage 4 GFR 15 to 29 ml/minute/1.73 m 2 , and stage 5 GFR <15 ml/min- ute/1.73 m 2 . CKD has become a global health issue. In the United States, the number of patients on Medicare- funded dialysis has undergone an exponential growth from ;10,000 patients in 1973 to 472,099 in 2004. 4 This increase in patient volume is attributed primarily to the number of new patients initiating dialysis (inci- dence) and less on an increase in patient survival (prevalence). Recent epidemiologic studies have seen a slowing of this growth in which the inci- dence of end-stage renal disease (ESRD) has in fact plateaued. 5 A reduction in the number of nephrons or a reduc- tion in the function of nephrons will reduce the GFR and could eventually lead to ESRD and the initiation of dialysis. Typically, in the chronic setting, dialysis is initiated once the GFR has fallen below 15 ml/minute/ 1.73 m 2 irrespective of the cause of renal failure. Al- though CKD has many causes, diabetic nephropathy (caused by uncontrolled type 1 or type 2 diabetes mel- litus) accounts for almost 44% of all ESRD cases and remains one of the leading causes of CKD followed by hypertensive nephrosclerosis in the United States. Other causes of CKD include glomerulonephritis (nephritic/nephrotic syndrome), interstitial nephritis, unresolved acute tubular necrosis, toxicity from expo- sure to chemicals or drugs, obstructive uropathy, nephrolithiasis, and effects from systemic diseases such as systemic lupus erythematosis, scleroderma, and multiple myeloma. Analysis of the Third National Health and Nutrition Examination estimated that up to 19 million Americans have CKD with 350,000 patients currently on dialysis. 6 There is evidence to support a mechanistic link among inflammation, atherosclerosis, and CKD. 4,7 Inflammatory biomarkers, such as C-reactive protein and interleukin-6, have been shown to be elevated in CKD. Diseases showing low-grade inflammation, such as diabetes and hypertension, are commonly as- sociated with CKD. Furthermore, dyslipidemia also contributes to the inflammatory response and is asso- ciated with atherosclerosis and CKD. Control of dys- lipidemia, especially with the use of statins, reduces proteinuria. Low-level inflammation increases expo- sure to oxidative stress via elevation of reactive oxy- gen species and reduced levels of antioxidants. Chronic periodontal inflammation may also con- tribute to the chronic systemic inflammatory burden associated with CKD. It is interesting to note that C-reactive protein, a marker for inflammation in doi: 10.1902/jop.2008.080313 * Department of Oral Biology, School of Dental Medicine, University at Buffalo, Buffalo, NY. † Department of Medicine, School of Medicine, University at Buffalo. J Periodontol • September 2008 1617
Transcript
Commentary
Periodontitis and Chronic Kidney Disease
Frank A. Scannapieco* and Mandip Panesar†
Since the late 1980s, there has been a growingliterature that suggests that periodontal dis-eases may contribute to a variety of significant
acute and chronic systemic diseases. Although theconnections between periodontal disease and athero-sclerosis, heart disease, and stroke have been wellpublicized, other potentially significant connectionshave been made with diabetes, obstetric complica-tions, respiratory disease, Alzheimer’s disease, andother diseases.1 A biologically plausible common linkbetween periodontal diseases and many systemicdiseases appears to be infection and inflammation.
This issue of the Journal of Periodontology presentsan article that makes the case for a connection be-tween periodontal diseases and chronic kidney disease(CKD).1
CKD is a catchall term for a variety of chronic con-ditions that result in compromised kidney function,which is measured as the glomerular filtration rate(GFR).
The gold standard to determine the GFR in patientsis to measure the clearance of insulin since it is notsecreted by the renal tubules, but this remains an im-practical test to perform clinically. Therefore, clini-cians have relied on the measurement of serumcreatinine as an indirect measure of the GFR anduse creatinine-based formulae to calculate the GFR.There is a high degree of physiologic variability inGFR among normal individuals, thus making it diffi-cult to define limits for normal GFR. The guidelines de-veloped by the National Kidney Foundation’s KidneyDisease and Outcomes Quality Initiative (K/DOQI)3
have defined five stages of CKD on the basis of differ-ent ranges of GFR: stage 1 GFR >90 ml/minute/1.73m2, stage 2 GFR 60 to 89 ml/minute/1.73 m2, stage 3GFR 30 to 59 ml/minute/1.73 m2, stage 4 GFR 15 to29 ml/minute/1.73 m2, and stage 5 GFR <15 ml/min-ute/1.73 m2.
CKD has become a global health issue. In theUnited States, the number of patients on Medicare-funded dialysis has undergone an exponential growthfrom ;10,000 patients in 1973 to 472,099 in 2004.4
This increase in patient volume is attributed primarily
to the number of new patients initiating dialysis (inci-dence) and less on an increase in patient survival(prevalence). Recent epidemiologic studies haveseen a slowing of this growth in which the inci-dence of end-stage renal disease (ESRD) has in factplateaued.5
A reduction in the number of nephrons or a reduc-tion in the function of nephrons will reduce the GFRand could eventually lead to ESRD and the initiationof dialysis. Typically, in the chronic setting, dialysis isinitiated once the GFR has fallen below 15 ml/minute/1.73 m2 irrespective of the cause of renal failure. Al-though CKD has many causes, diabetic nephropathy(caused by uncontrolled type 1 or type 2 diabetes mel-litus) accounts for almost 44% of all ESRD cases andremains one of the leading causes of CKD followedby hypertensive nephrosclerosis in the United States.
Other causes of CKD include glomerulonephritis(nephritic/nephrotic syndrome), interstitial nephritis,unresolved acute tubular necrosis, toxicity from expo-sure to chemicals or drugs, obstructive uropathy,nephrolithiasis, and effects from systemic diseasessuch as systemic lupus erythematosis, scleroderma,and multiple myeloma.
Analysis of the Third National Health and NutritionExamination estimated thatup to19 millionAmericanshave CKD with 350,000 patients currently on dialysis.6
There is evidence to support a mechanistic linkamong inflammation, atherosclerosis, and CKD.4,7
Inflammatory biomarkers, such as C-reactive proteinand interleukin-6, have been shown to be elevated inCKD. Diseases showing low-grade inflammation,such as diabetes and hypertension, are commonly as-sociated with CKD. Furthermore, dyslipidemia alsocontributes to the inflammatory response and is asso-ciated with atherosclerosis and CKD. Control of dys-lipidemia, especially with the use of statins, reducesproteinuria. Low-level inflammation increases expo-sure to oxidative stress via elevation of reactive oxy-gen species and reduced levels of antioxidants.
Chronic periodontal inflammation may also con-tribute to the chronic systemic inflammatory burdenassociated with CKD. It is interesting to note thatC-reactive protein, a marker for inflammation in
doi: 10.1902/jop.2008.080313
* Department of Oral Biology, School of Dental Medicine, University atBuffalo, Buffalo, NY.
† Department of Medicine, School of Medicine, University at Buffalo.
J Periodontol • September 2008
1617
blood, has been shown to be elevated in both peri-odontal and CKDpatients.8 Given the potential forperi-odontal disease to contribute to the etiology of CKD, itis not surprising to find several studies that have at-tempted to link oral inflammation and CKD. However,thereare rather fewpublished large-scaleepidemiologicor case-control studies that compared the oral healthstatus of patients with CKD with a control group withnormal renal function.
For example, Kshirsagar et al.9 performed a cross-sectional study of 5,537 middle-aged black and whitemen and women. One hundred ten individuals (2%)had a GFR <60 ml/minute/1.73 m2. These investiga-tors found that this GFR level was associated with mildperiodontal disease (odds ratio, 2.00; 95% confidenceinterval, 1.23 to 3.24) and severe periodontal disease(odds ratio of 2.14; 95% confidence interval, 1.19 to3.85) after adjustment for important risk factors forcardiovascular disease and CKD. A follow-up study10
from the same group examined the associations ofkidney disease with serum antibody to oral pathogensin a cohort of older community-dwelling subjects en-rolled in the Dental Atherosclerosis Risk in Communi-ties study. High levels of serum immunoglobulin G totarget periodontal pathogens, including Porphyromo-nas gingivalis, Treponema denticola, and Aggregati-bacter actinomycetemcomitans (Aa; previouslyActinobacillus actinomycetemcomitans), were asso-ciated with an increased risk for patients having aGFR <60 ml/min/1.73 m2.
In another study,11 Davidovich et al. compared fivegroups with respect to oral health status: 22 subjectswith chronic renal disease; 22 undergoing dialysis; 21who initially were on dialysis and then had a kidneytransplant; 32 with kidney transplants and 32 healthycontrols. The renal failure groups had more gingivalinflammation, deeper periodontal probing depths,more periodontal attachment loss, more pulp obliter-ation, and fewer caries than the periodontally healthycontrols. Patients with ESRD and on dialysis had a sig-nificant correlation with gingivitis, probing depth, at-tachment loss, and enamel hypoplasia.
Shultis et al.12 investigated members of the GilaRiver Indian Community in Arizona for an associationbetween periodontitis and CKD in type 2 diabetes.Age- and gender-adjusted incidence of macroalbu-minuria and ESRD increased with the severity ofperiodontitis. Risk models adjusted for age, gender, di-abetes duration, body mass index, and smokingshowed incidences of macroalbuminuria were 2.0,2.1, and 2.6 times as high in individuals with moderateor severe periodontitis or those who were edentulous,respectively, compared to those with none/mild peri-odontitis.
A study13 of a Japanese cohort of 77 elders foundthat the percentage of clinical attachment level ‡6
mm was significantly associated with renal functionand bone metabolism markers. This study suggestedthat the increased incidence of chronic renal failurethat occurs with age might increase the probabilityof severe periodontal disease in community-dwellingelderly subjects.
Finally, Borawski et al.14 compared 106 dialysisand CKD subjects to a group of 26 systemicallyhealthy periodontitis subjects and another group of30 subjects from the general population. Their resultsshowed more severe periodontitis in the renal-failuregroups compared to the systemically normal sub-jects.
Although the evidence in support of an associationbetween periodontitis and CKD is increasing, not allstudies demonstrate a positive association. For ex-ample, Castillo et al.15 found no association betweenESRD and severe periodontitis.
The study by Fisher et al.,2 published in this issue ofthe Journal, supports the positive association be-tween a history of periodontitis and CKD. The strengthof the study includes the fact that a large study popu-lation (over 4,000) was investigated. However, the re-sults reported must be interpreted with some caution.First, it is a cross-sectional study, and, therefore, noconclusions on cause and effect can be rendered. Fur-thermore, the parameters used to define periodontaldisease were very liberal (one pocket >4 mm). Thisis unusual since the vast majority of articles use amore specific definition of periodontal disease (typi-cally, multiple pockets >5 mm). Although Fisher et al.suggest the host inflammatory burden is ultimatelyresponsible for the kidney disease, only clinical toothloss was positively associated with CKD, and Aa an-tibody levels were actually negatively associated. Itis unlikely that most edentulous individuals have se-vere oral inflammation (although mild denture stoma-titis is a common finding among elders). The authorsfail to discuss a mechanism by which a high anti-Aatiter would protect against CKD.
These concerns notwithstanding, the results of theinvestigation support previous findings of an associa-tion between CKD and periodontal disease. As thereappear to be connections between periodontitis andCKD, as well as between CKD and atherosclerosisand periodontitis and atherosclerosis, further investi-gations that attempt to define the mechanisms thatlink these conditions are justified.
ACKNOWLEDGMENT
The authors report no conflicts of interest related tothis commentary.
REFERENCES1. Scannapieco FA. Systemic effects of periodontal dis-
eases. Dent Clin North Am 2005;49:533-550, vi.
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2. Fisher MA, Taylor GW, Papapanou PN, Rahman M,Debanne SM. Clinical and serologic markers of peri-odontal infection and chronic kidney disease. J Peri-odontol 2008;79:1670-1678.
3. Hogg RJ, Furth S, Lemley KV, et al. National KidneyFoundation’s Kidney Disease Outcomes Quality Ini-tiative clinical practice guidelines for chronic kidneydisease in children and adolescents: Evaluation, clas-sification, and stratification. Pediatrics 2003;111:1416-1421.
4. Schiffrin EL, Lipman ML, Mann JF. Chronic kidneydisease: Effects on the cardiovascular system. Circu-lation 2007;116:85-97.
6. Coresh J, Astor BC, Greene T, Eknoyan G, Levey AS.Prevalence of chronic kidney disease and decreasedkidney function in the adult US population: Third Na-tional Health and Nutrition Examination Survey. Am JKidney Dis 2003;41:1-12.
7. Kovesdy CP, Kalantar-Zadeh K. Novel targets and newpotential: Developments in the treatment of inflam-mation in chronic kidney disease. Expert Opin InvestigDrugs 2008;17:451-467.
8. Stenvinkel P. Inflammation in end-stage renal disease:the hidden enemy. Nephrology (Carlton) 2006;11:36-41.
9. Kshirsagar AV, Moss KL, Elter JR, Beck JD, OffenbacherS, Falk RJ. Periodontal disease is associated with renalinsufficiency in the Atherosclerosis Risk In Communi-ties (ARIC) study. Am J Kidney Dis 2005;45:650-657.
10. Kshirsagar AV, Offenbacher S, Moss KL, Barros SP,Beck JD. Antibodies to periodontal organisms are as-sociated with decreased kidney function. The DentalAtherosclerosis Risk In Communities study. Blood Purif2007;25:125-132.
11. Davidovich E, Schwarz Z, Davidovitch M, Eidelman E,Bimstein E. Oral findings and periodontal status inchildren, adolescents and young adults suffering fromrenal failure. J Clin Periodontol 2005;32:1076-1082.
12. Shultis WA, Weil EJ, Looker HC, et al. Effect of peri-odontitis on overt nephropathy and end-stage renaldisease in type 2 diabetes. Diabetes Care 2007;30:306-311.
13. Yoshihara A, Deguchi T, Hanada N, Miyazaki H. Renalfunction and periodontal disease in elderly Japanese.J Periodontol 2007;78:1241-1248.
14. Borawski J, Wilczynska-Borawska M, Stokowska W,Mysliwiec M. The periodontal status of pre-dialysischronic kidney disease and maintenance dialysis pa-tients. Nephrol Dial Transplant 2007;22:457-464.
15. Castillo A, Mesa F, Liebana J, et al. Periodontal andoral microbiological status of an adult populationundergoing haemodialysis: A cross-sectional study.Oral Dis 2007;13:198-205.
Correspondence: Dr. Frank A. Scannapieco, Departmentof Oral Biology, School of Dental Medicine, University atBuffalo, Foster Hall, Buffalo, NY 14214. Fax: 716/829-3942; e-mail: [email protected].
Submitted June 8, 2008; accepted for publication June 8,2008.
J Periodontol • September 2008 Scannapieco, Panesar
