- Email: [email protected]
Periodontitis May Be Associated With Chronic Kidney Disease, but Evidence on Causal Association Is Limited
The Journal of EVIDENCE-BASED DENTAL PRACTICE
REVIEW ANALYSIS & EVALUATION // DIAGNOSIS/TREATMENT/PROGNOSIS
PERIODONTITIS MAY BE ASSOCIATED WITH CHRONIC KIDNEY DISEASE, BUT EVIDENCE ON CAUSAL ASSOCIATION IS LIMITED Do patients with periodontitis have a higher risk of developing chronic kidney disease? REVIEWERS
SHANIKA NANAYAKKARA, XIAOYAN ZHOU
A
SORT SCORE B C
N/A
SORT, Strength of Recommendation Taxonomy.
LEVEL OF EVIDENCE 1 2 3 See page 8A for complete details regarding SORT and LEVEL OF EVIDENCE grading system.
SOURCE OF FUNDING The authors’ own institution, University of Hong Kong.
ARTICLE TITLE AND BIBLIOGRAPHIC INFORMATION The directional and nondirectional associations of periodontitis with chronic kidney disease: A systematic review and meta-analysis of observational studies. Zhao D, Khawaja AT, Jin L, Li K–Y, Tonetti M, Pelekos G. J Perio Res 2018; 53(5):682-704.
SUMMARY The authors conducted a systematic review and meta-analysis of observational studies on the directional and nondirectional association between periodontitis and chronic kidney disease (CKD).
Study Selection TYPE OF STUDY/DESIGN Systematic review with meta-analysis of data.
KEYWORDS Chronic kidney disease, Epidemiology, Meta-analysis, Periodontal disease, Periodontitis, Systematic review
Authors searched 5 electronic databases (Medline, Embase, PubMed, Cochrane Library, and OpenGrey) up to June 2017 for cohort, case-control, and crosssectional studies. Based on the inclusion and exclusion criteria, 47 articles (2 cohort studies, 7 case-control studies, and 38 cross-sectional studies) that investigated the association between periodontitis and CKD were included in the review. Among the included studies, only 2 retrospective cohort studies investigated the directional association of periodontitis with CKD. Methodological quality assessment indicated only 12 of the included studies were of moderate to high quality. The authors conducted a meta-analysis to estimate the pooled odds ratio for nondirectional association and the incidence rate ratio (IRR) for the directional association using the data of 6 articles (3 cross-sectional, 1 casecontrol, and 2 retrospective cohort studies).
Key Study Factor The key study factor of the review was periodontitis. The definition of periodontitis was based on at least 1 clinical periodontal parameter (community periodontal index, clinical attachment loss, or periodontal probing depth). J Evid Base Dent Pract 2019: [192-194] 1532-3382/$36.00 ª 2019 Elsevier Inc. All rights reserved. doi: https://doi.org/10.1016/ j.jebdp.2019.05.014
192
Volume 19, Number 2
Main Outcome Measure The main outcome measure of the review was CKD. Articles with a diagnosis of CKD or definition of CKD based on serum and/or urine parameters or no definition of CKD but with reported estimated glomerular filtration rate (eGFR) were considered relevant in the article-selection process.
The Journal of EVIDENCE-BASED DENTAL PRACTICE
Main Results Most of the included articles reported a nondirectional association between periodontitis and CKD. Seventy-five percent of the articles with a statistical analysis (18 of 24) reported a significant nondirectional association. However, the authors reported a substantial variation in the prevalence of periodontitis among patients with CKD (12.3%-96.6%). Analysis of data from 4 studies for the nondirectional association showed that the subjects with periodontitis had 3.54 (95% confidence interval [CI], 2.175.77; P , .001) times higher odds of having CKD than the subjects without periodontitis. However, heterogeneity of the included studies was statistically significant (I2 5 88.3%; P , .001). Two retrospective cohort studies that investigated the directional association of periodontitis with CKD provided conflicting, inconclusive evidence. The random-effects model resulted an IRR of 2.10 (95% CI, 0.72-6.15; P 5 .177), whereas the fixed-effect model resulted in an IRR of 1.76 (95% CI, 1.11-2.77; P 5 .016). Heterogeneity of the studies was reported to be statistically significant (I2 5 78.3%; P 5 .031).
Conclusions The authors concluded that the evidence supports a nondirectional association between periodontitis and CKD. It was emphasized that the evidence on a directional association is sparse. Future investigations using prospective studies with representative samples and longer follow-up periods are required.
COMMENTARY AND ANALYSIS CKD is defined as having an eGFR less than 60 mL per minute (per 1.73 m2) for more than 3 months or evidence of renal tissue damage for more than 3 months, regardless of the eGFR.1 The global prevalence of CKD is increasing steadily, and it has been identified as one of the major chronic noncommunicable diseases that require expensive and resource-intensive management.2 A recent report released by the World Health Organization notes that 2.62 million people received dialysis in 2010 and projections of the need should double by 2030.3 Thus, it is important to identify the modifiable risk factors to effectively prevent the onset and progression of CKD. The purpose of this systematic review with meta-analysis was to evaluate the association of CKD with periodontitis, which is a highly prevalent chronic inflammatory condition caused by pathogenic oral microflora. The evidence summarized sheds some light on this important topic and emphasizes the value of future investigations to further evaluate the association between these 2 disease entities. The review was carefully conducted using Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. The authors
searched for both published and unpublished evidence relevant to the topic. However, assessing the quality of evidence provided raises some concerns. The authors also identified and reported some of the limitations of their review. A limited number of studies with evidence of moderate to high quality (25.5%) and the heterogeneous nature of the included articles affect the strength of the evidence provided by this review. In particular, the authors have identified only 2 retrospective cohort studies investigating the directional association of periodontitis with CKD, and those 2 studies have provided conflicting evidence. Either due to a lack of information or the use of similar data sources, the number of articles the authors could use for meta-analysis is low. It is important to note that the latest meta-analysis available on the association of periodontitis with CKD uses a relatively higher number of studies and reports a similar positive association but slightly lower odds ratio (1.88, 95% CI, 1.69-3.01) and an IRR of 1.73.4 A few more systematic reviews and meta-analyses were published before and after this article on the same topic. Some of the reviews evaluated the association of periodontitis with CKD, and some further evaluated the effects of periodontal treatment on renal function. Considering the available body of evidence, this article provides limited new information. It is important to note that none of the articles included in this review considered CKD as the exposure and periodontitis as the outcome even though previous investigations have reported on a bidirectional relationship between these 2 conditions.5 The limited quality of evidence provided in the review warrants future investigations to provide stronger, more conclusive evidence on any causal association between periodontitis and CKD. As the authors have identified, the inconsistency in the definition of CKD and periodontitis can have a substantial impact on study selection and results. Variations in both periodontal disease status and CKD stages among the study populations can also have a direct influence on the reported outcomes of the studies. Therefore, future investigations should use standard clinical guidelines to select the study participants and to define the exposure and outcome variables. Furthermore, it is noteworthy that both CKD and periodontitis are multifactorial diseases, thus several potential confounding factors that can have significant impact on the results need to be considered. Admittedly, the findings of this systematic review and metaanalysis are consistent with the available evidence on a nondirectional association between periodontitis and CKD, but the evidence provided on the potential role of periodontitis as a risk factor for CKD is weak.
June 2019
193
The Journal of EVIDENCE-BASED DENTAL PRACTICE
CLINICAL APPLICATION Similar to the high prevalence of CKD, periodontitis affects 20% to 50% of the world’s population and is considered as one of the 2 major threats to oral health.6 Considering the substantial burden of CKD and periodontitis in the aging population7,8 and the notable increase in the number of people aged 60 years or older in the recent years, it further highlights the importance of knowledge on the relationship between these 2 diseases.9 Careful analysis of the evidence provided in this systematic review and metaanalysis allows the conclusion that the provided evidence is not strong enough for the clinicians to make causal inferences on the association between periodontitis and CKD. Thus, future well-designed prospective studies are required to provide conclusive evidence on the potential role of periodontitis in the causation of CKD.
REFERENCES 1. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl 2013;3:1-150. 2. Thomas B, Matsushita K, Abate KH, et al. Global cardiovascular and renal outcomes of reduced GFR. J Am Soc Nephrol 2017;28(7):2167-79. 3. Luyckx VA, Tonelli M, Stanifer JW. The global burden of kidney disease and the sustainable development goals. Bull WHO 2018;96(6):414.
194
Volume 19, Number 2
4. Deschamps-Lenhardt S, Martin-Cabezas R, Hannedouche T, Huck O. Association between periodontitis and chronic kidney disease: systematic review and meta-analysis. Oral Dis 2018;25(2):385-402. 5. Wahid A, Chaudhry S, Ehsan A, Butt S, Khan AA. Bidirectional relationship between chronic kidney disease & periodontal disease. Pakistan J Med Sci 2013;29(1):211. 6. Nazir MA. Prevalence of periodontal disease, its association with systemic diseases and prevention. Int J Health Sci 2017;11(2):72. 7. Tonelli M, Riella M. Chronic kidney disease and the aging population. Am J Physiol Renal Physiol 2014;306(5):F469-72. 8. López R, Smith PC, Göstemeyer G, Schwendicke F. Ageing, dental caries and periodontal diseases. J Clin Periodontol 2017;44:S145-52. 9. United Nations, Department of Economic and Social Affairs, Population Division. World Population Ageing 2015. 2015. (ST/ ESA/SER.A/390).
REVIEWERS SHANIKA NANAYAKKARA, MBBS, PHD School of Dentistry, Faculty of Medicine and Health, The University of Sydney, NSW 2006, Australia, Shanika. [email protected] XIAOYAN ZHOU, BDS, MDS, PHD School of Dentistry, Faculty of Medicine and Health, The University of Sydney, NSW 2006, Australia, Xiaoyan.zhou@ sydney.edu.au
REVIEW ANALYSIS & EVALUATION // DIAGNOSIS/TREATMENT/PROGNOSIS
PERIODONTITIS MAY BE ASSOCIATED WITH CHRONIC KIDNEY DISEASE, BUT EVIDENCE ON CAUSAL ASSOCIATION IS LIMITED Do patients with periodontitis have a higher risk of developing chronic kidney disease? REVIEWERS
SHANIKA NANAYAKKARA, XIAOYAN ZHOU
A
SORT SCORE B C
N/A
SORT, Strength of Recommendation Taxonomy.
LEVEL OF EVIDENCE 1 2 3 See page 8A for complete details regarding SORT and LEVEL OF EVIDENCE grading system.
SOURCE OF FUNDING The authors’ own institution, University of Hong Kong.
ARTICLE TITLE AND BIBLIOGRAPHIC INFORMATION The directional and nondirectional associations of periodontitis with chronic kidney disease: A systematic review and meta-analysis of observational studies. Zhao D, Khawaja AT, Jin L, Li K–Y, Tonetti M, Pelekos G. J Perio Res 2018; 53(5):682-704.
SUMMARY The authors conducted a systematic review and meta-analysis of observational studies on the directional and nondirectional association between periodontitis and chronic kidney disease (CKD).
Study Selection TYPE OF STUDY/DESIGN Systematic review with meta-analysis of data.
KEYWORDS Chronic kidney disease, Epidemiology, Meta-analysis, Periodontal disease, Periodontitis, Systematic review
Authors searched 5 electronic databases (Medline, Embase, PubMed, Cochrane Library, and OpenGrey) up to June 2017 for cohort, case-control, and crosssectional studies. Based on the inclusion and exclusion criteria, 47 articles (2 cohort studies, 7 case-control studies, and 38 cross-sectional studies) that investigated the association between periodontitis and CKD were included in the review. Among the included studies, only 2 retrospective cohort studies investigated the directional association of periodontitis with CKD. Methodological quality assessment indicated only 12 of the included studies were of moderate to high quality. The authors conducted a meta-analysis to estimate the pooled odds ratio for nondirectional association and the incidence rate ratio (IRR) for the directional association using the data of 6 articles (3 cross-sectional, 1 casecontrol, and 2 retrospective cohort studies).
Key Study Factor The key study factor of the review was periodontitis. The definition of periodontitis was based on at least 1 clinical periodontal parameter (community periodontal index, clinical attachment loss, or periodontal probing depth). J Evid Base Dent Pract 2019: [192-194] 1532-3382/$36.00 ª 2019 Elsevier Inc. All rights reserved. doi: https://doi.org/10.1016/ j.jebdp.2019.05.014
192
Volume 19, Number 2
Main Outcome Measure The main outcome measure of the review was CKD. Articles with a diagnosis of CKD or definition of CKD based on serum and/or urine parameters or no definition of CKD but with reported estimated glomerular filtration rate (eGFR) were considered relevant in the article-selection process.
The Journal of EVIDENCE-BASED DENTAL PRACTICE
Main Results Most of the included articles reported a nondirectional association between periodontitis and CKD. Seventy-five percent of the articles with a statistical analysis (18 of 24) reported a significant nondirectional association. However, the authors reported a substantial variation in the prevalence of periodontitis among patients with CKD (12.3%-96.6%). Analysis of data from 4 studies for the nondirectional association showed that the subjects with periodontitis had 3.54 (95% confidence interval [CI], 2.175.77; P , .001) times higher odds of having CKD than the subjects without periodontitis. However, heterogeneity of the included studies was statistically significant (I2 5 88.3%; P , .001). Two retrospective cohort studies that investigated the directional association of periodontitis with CKD provided conflicting, inconclusive evidence. The random-effects model resulted an IRR of 2.10 (95% CI, 0.72-6.15; P 5 .177), whereas the fixed-effect model resulted in an IRR of 1.76 (95% CI, 1.11-2.77; P 5 .016). Heterogeneity of the studies was reported to be statistically significant (I2 5 78.3%; P 5 .031).
Conclusions The authors concluded that the evidence supports a nondirectional association between periodontitis and CKD. It was emphasized that the evidence on a directional association is sparse. Future investigations using prospective studies with representative samples and longer follow-up periods are required.
COMMENTARY AND ANALYSIS CKD is defined as having an eGFR less than 60 mL per minute (per 1.73 m2) for more than 3 months or evidence of renal tissue damage for more than 3 months, regardless of the eGFR.1 The global prevalence of CKD is increasing steadily, and it has been identified as one of the major chronic noncommunicable diseases that require expensive and resource-intensive management.2 A recent report released by the World Health Organization notes that 2.62 million people received dialysis in 2010 and projections of the need should double by 2030.3 Thus, it is important to identify the modifiable risk factors to effectively prevent the onset and progression of CKD. The purpose of this systematic review with meta-analysis was to evaluate the association of CKD with periodontitis, which is a highly prevalent chronic inflammatory condition caused by pathogenic oral microflora. The evidence summarized sheds some light on this important topic and emphasizes the value of future investigations to further evaluate the association between these 2 disease entities. The review was carefully conducted using Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. The authors
searched for both published and unpublished evidence relevant to the topic. However, assessing the quality of evidence provided raises some concerns. The authors also identified and reported some of the limitations of their review. A limited number of studies with evidence of moderate to high quality (25.5%) and the heterogeneous nature of the included articles affect the strength of the evidence provided by this review. In particular, the authors have identified only 2 retrospective cohort studies investigating the directional association of periodontitis with CKD, and those 2 studies have provided conflicting evidence. Either due to a lack of information or the use of similar data sources, the number of articles the authors could use for meta-analysis is low. It is important to note that the latest meta-analysis available on the association of periodontitis with CKD uses a relatively higher number of studies and reports a similar positive association but slightly lower odds ratio (1.88, 95% CI, 1.69-3.01) and an IRR of 1.73.4 A few more systematic reviews and meta-analyses were published before and after this article on the same topic. Some of the reviews evaluated the association of periodontitis with CKD, and some further evaluated the effects of periodontal treatment on renal function. Considering the available body of evidence, this article provides limited new information. It is important to note that none of the articles included in this review considered CKD as the exposure and periodontitis as the outcome even though previous investigations have reported on a bidirectional relationship between these 2 conditions.5 The limited quality of evidence provided in the review warrants future investigations to provide stronger, more conclusive evidence on any causal association between periodontitis and CKD. As the authors have identified, the inconsistency in the definition of CKD and periodontitis can have a substantial impact on study selection and results. Variations in both periodontal disease status and CKD stages among the study populations can also have a direct influence on the reported outcomes of the studies. Therefore, future investigations should use standard clinical guidelines to select the study participants and to define the exposure and outcome variables. Furthermore, it is noteworthy that both CKD and periodontitis are multifactorial diseases, thus several potential confounding factors that can have significant impact on the results need to be considered. Admittedly, the findings of this systematic review and metaanalysis are consistent with the available evidence on a nondirectional association between periodontitis and CKD, but the evidence provided on the potential role of periodontitis as a risk factor for CKD is weak.
June 2019
193
The Journal of EVIDENCE-BASED DENTAL PRACTICE
CLINICAL APPLICATION Similar to the high prevalence of CKD, periodontitis affects 20% to 50% of the world’s population and is considered as one of the 2 major threats to oral health.6 Considering the substantial burden of CKD and periodontitis in the aging population7,8 and the notable increase in the number of people aged 60 years or older in the recent years, it further highlights the importance of knowledge on the relationship between these 2 diseases.9 Careful analysis of the evidence provided in this systematic review and metaanalysis allows the conclusion that the provided evidence is not strong enough for the clinicians to make causal inferences on the association between periodontitis and CKD. Thus, future well-designed prospective studies are required to provide conclusive evidence on the potential role of periodontitis in the causation of CKD.
REFERENCES 1. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl 2013;3:1-150. 2. Thomas B, Matsushita K, Abate KH, et al. Global cardiovascular and renal outcomes of reduced GFR. J Am Soc Nephrol 2017;28(7):2167-79. 3. Luyckx VA, Tonelli M, Stanifer JW. The global burden of kidney disease and the sustainable development goals. Bull WHO 2018;96(6):414.
194
Volume 19, Number 2
4. Deschamps-Lenhardt S, Martin-Cabezas R, Hannedouche T, Huck O. Association between periodontitis and chronic kidney disease: systematic review and meta-analysis. Oral Dis 2018;25(2):385-402. 5. Wahid A, Chaudhry S, Ehsan A, Butt S, Khan AA. Bidirectional relationship between chronic kidney disease & periodontal disease. Pakistan J Med Sci 2013;29(1):211. 6. Nazir MA. Prevalence of periodontal disease, its association with systemic diseases and prevention. Int J Health Sci 2017;11(2):72. 7. Tonelli M, Riella M. Chronic kidney disease and the aging population. Am J Physiol Renal Physiol 2014;306(5):F469-72. 8. López R, Smith PC, Göstemeyer G, Schwendicke F. Ageing, dental caries and periodontal diseases. J Clin Periodontol 2017;44:S145-52. 9. United Nations, Department of Economic and Social Affairs, Population Division. World Population Ageing 2015. 2015. (ST/ ESA/SER.A/390).
REVIEWERS SHANIKA NANAYAKKARA, MBBS, PHD School of Dentistry, Faculty of Medicine and Health, The University of Sydney, NSW 2006, Australia, Shanika. [email protected] XIAOYAN ZHOU, BDS, MDS, PHD School of Dentistry, Faculty of Medicine and Health, The University of Sydney, NSW 2006, Australia, Xiaoyan.zhou@ sydney.edu.au