Effect of periodontal treatment on the glomerular filtration rate, reduction of inflammatory markers and mortality in patients with chronic kidney disease: A systematic review

Aim To assess the effect of periodontal treatment (PT) on glomerular filtration rate (GFR), systemic inflammation, or mortality in patients with chronic kidney disease (CKD). Methods A literature search was performed on PubMed and Web of Science databases on articles published until December 2019. The PRISMA guidelines were used throughout the manuscript. Results Of the total studies found, only 18 met the inclusion criteria; four retrospective and 14 prospective studies (including 3 randomized controlled trials–RCT). After PT, 3 studies investigated GFR, 2 found significant improvement; 11 (including 2 RCTs) investigated C-reactive protein levels, 9 found a significant improvement (including the 2 RCTs); 5 (including 3 RCTs) investigated Interleukine-6 level, 4 found a significant improvement (including 2 RCTs) and 2 studies evaluated mortality, one (retrospective study) found a significant difference. Conclusions Within the limitations of the present study, PT seems to improve CKD status, especially by reducing the systemic inflammation. Further RCTs are needed to confirm the results and specifically assess the influence of different types of PT in CKD patients. Taking into consideration the ability of PT to prevent further tooth loss and denutrition, early management of periodontitis is extremely important in patients with impaired renal function.


Introduction
Periodontitis is an immune-mediated inflammatory disease that is due to bacterial infection (periodontal flora), leading to the destruction of the tissues surrounding the tooth (periodontium). The global prevalence of its severe forms has been estimated to 10.8%, affecting 743 million people worldwide [1]. Both innate and adaptive immune responses are stimulated by the periodontal bacteria [2] and the release of bacterial products and inflammatory mediators from periodontal pockets result in low-grade systemic inflammation [3,4]. Periodontitis has been most strongly associated with an increase of pro-inflammatory cytokines levels [5] and serum C-reactive protein (CRP) levels [6]. Moreover, the relationship between periodontitis and some systemic diseases has been well documented (for example periodontitis and diabetes [7,8], periodontitis and cardiovascular diseases [9,10]). There is also strong evidence supporting a positive association between periodontitis and chronic kidney disease (CKD) [11][12][13], and some studies suggest a more severe periodontal breakdown with the progression of kidney disease [14,15], and the duration of dialysis therapy [16]. Furthermore, the risk of death is higher in haemodialysis (end-stage renal disease) patients with periodontitis than those without periodontitis [17,18]. If relationship between these two diseases is often described, recent meta-analysis concluded that there is a need to determine whether prevention of periodontal disease or periodontal treatment can reduce the severity of CKD [11,19]. CKD is related to many specifics markers: diagnostic of CKD is based on the glomerular filtration rate (GFR) levels, also CKD have an influence in inflammatory markers, and is related to death due to cardio-vascular disease. We aimed to systematically review all prospective and retrospective studies assessing the effect of periodontal treatment in CKD using clinical parameters, in patients suffering of periodontitis.

Materials and methods
The preferred reporting items for systematic reviews and meta-analyses (PRISMA) [20] were used as a guideline throughout the manuscript and the protocol was registered in the international prospective register of systematic reviews (PROSPERO; registration number CRD42017075376).

Study selection
The inclusion criteria were: at least one group of patients with periodontitis and CKD at any stage, including end-stage-renal disease (ESRD); any kind of PT, including oral hygiene instruction, nonsurgical or surgical treatment; and at least one of the following-renal function evaluation (i.e. GFR), inflammatory marker, or mortality.

Search strategy
A literature search was performed using two electronic databases (PubMed & Web of Science) on articles published until December 2019. Language restrictions were not applied. The keywords used in the electronic search (in "Title/Abstract" for MEDLINE database and "Topic" for Web of Science database) were as follows: periodont � AND (oral hygiene OR root planing OR treatment OR therapy) AND (end-stage renal disease OR renal failure OR chronic kidney disease OR hemodialysis OR dialysis) Authors (TD, KG) independently reviewed and screened the title and abstract of potentially relevant records and determined final eligibility through examination of full texts. Citations were screened for additional publications that were missed by the electronic search. Review articles and short communications were excluded. Disagreements were resolved through discussion.

Data collection
Our analysis focused for each study on the protocol parameters, the assessment criteria, the comparison groups, and the biological and clinical results. To determine the bias of studies, the Cochrane risk of bias tool was used for RCTs [21]; two reviewers (TD, PN) assigned a judgment of high, low, or unclear risk of material bias for each item independently. Discrepancies about risk of each risk of bias have been resolved by discussion in the first instance; where consensus could not be reached, a third reviewer was consulted. The quality of each non-randomized study (including at least one control group) was evaluated using the Newcastle-Ottawa Scale [22]. This scale includes 3 categorical criteria with a maximum score of 9 points: the selection of the study groups; the comparability of the groups; and the ascertainment of the outcome of interest. The quality of each study was rated using the following scoring algorithms: �7 points was considered as "high", 4 to 6 points was considered as "moderate", and �3 point was considered as "poor" quality study.
In the retrospective studies, three estimated the risk of complications of patients with endstage renal disease, periodontitis and periodontal treatment (experimental group) versus endstage renal disease (control group) [39][40][41] and the other estimated the incidence and risk of ESRD in patients with periodontitis and periodontal treatment (experimental group) versus patients with periodontal disease only (without periodontal treatment) ( Table 1) [42].
There was no significant correlation between periodontal parameters and albumin and creatinine levels. After completion of periodontal therapy (duration 6 ± 2 weeks): Significant decrease of hs-CRP (p < 0.001) and erythropoeitin (p< 0.01), and significant increase of blood urea nitrogen (p< 0.01) and albumin (p< 0.001). No statistical differences (p< 0.05) observed in the other parameters.

Interventional uncontrolled study
No control group Single center study Exploratory results In both groups, significantly decreases were observed for the following parameters ; prohepcidin (p < 0.05 and p < 0.01 for experimental and control groups, respectively), IL-6 (p < 0.01 and p < 0.05 for experimental and control groups, respectively) and us-CRP (p < 0.01 and p < 0.05 for experimental and control groups, respectively). In the control group, a significant increase in the levels of hemoglobin (p < 0.05) and ferritin (p < 0.05) was also observed.

Interventional controlled non-randomized
For the 4 retrospectives studies [39][40][41][42], the authors included patients who underwent for periodontal treatment. No evaluation of the periodontal treatment effectiveness was mentioned.

Clinical outcomes
Among the 11 studies evaluating CRP levels, 9 showed a significant improvement after periodontal treatment either with respect to baseline [26, 27, 29, 31-33, 35, 36, 38] or to a control group [29]. For IL-6 level, 4 studies (on 5 studies) showed a significant decrease after periodontal treatment compared to baseline [26,27,29,36]. RCT studies comparing experimental groups (ESRD and periodontitis and PT) to control groups (ESRD and PT) were Fang et al.
[29] and Wehmeyer et al. [34]. At 3 and 6 months after completion of periodontal treatment, a significant decrease of IL-6 level was demonstrated in the first study [29] whereas no significant differences were observed in the second one (Table 1) [34].
The two studies investigating GFR as primary endpoint found a significant increase after periodontal treatment as compared to baseline [28, 37] without significant differences between the experimental group (CKD and periodontitis and PT) and the control group (PD and PT) ( Table 1) [37].
Among the 4 retrospective studies, one found that the incidence of ESRD was 37% lower in the treatment group (PD and PT) than in the non-treatment group (PD without PT) with an adjusted HR of 0.59 (95% CI = 0.46 to 0.75) [42], and the three other found that patients with ESRD and periodontitis receiving periodontal treatment had a significantly lower risk of acute and subacute infective endocarditis, pneumonia, and osteomyelitis [41], and of cardiovascular diseases and mortality [39,40] than patients with ESRD only (Table 1).
In the prospective study investigating the effect of treatment on fatal events, no significant difference was found between the groups after adjustments for confounders (Table 1) [30].
The 3 RCTs could be used for the Cochrane collaboration's tool for assessing risk of bias in randomized trials. Two studies showed high risk of bias concerned blinding conditions (  According to the Newcastle-Ottawa Scale, the quality of the 4 prospective studies including at least one control group and of the 4 retrospective studies were considered as moderate quality [26,30,37] and the others as high quality [36,[39][40][41][42] (Table 5).
The 7 prospective studies having no control group were considered at high risk of bias.

Discussion
To the best of our knowledge, this is the first systematic review to have investigated the effect of periodontal treatment in CKD and periodontitis patients in terms of GFR, systemic inflammation, and morbidity and mortality. Some recent systematic review and meta-analysis have demonstrated an association between renal impairment and periodontitis [11,12,19], and pointed out the need of RCTs investigating the effect of prevention or periodontal treatment on the severity of renal dysfunction. Among the 14 prospective studies, only 3 were RCTs and 11 were non-randomized. The objective of the 3 randomized studies was to evaluate the effect of periodontal treatment on systemic inflammation. However, the periodontal treatment differed between each study: oral hygiene instructions and non-surgical periodontal treatment or oral hygiene instructions alone [27], oral hygiene instructions and non-surgical treatment and teeth extractions if necessary [29], or oral hygiene instructions and non-surgical treatment with adjunctive local-delivery antimicrobial therapy and teeth extraction if necessary [34]. Systemic inflammation as assessed by hs-CRP [27,29] or IL-6 [34] was the primary endpoint. Two were restricted to ESRD patients [29,34], whereas the third study included all patients with a GFR<60 mL/ A: Representativeness of the exposed cohort; B: Selection of the non-exposed cohort; C: Ascertainment of exposure; D: Demonstration that outcome of interest was not present at start of study; E: Comparability of cohorts on the basis of the design or analysis; F: Assessment of outcome; G: Was follow-up long enough for outcomes to occur; H: Adequacy of follow up of cohorts.
https://doi.org/10.1371/journal.pone.0245619.t005  [34]. Despite the heterogeneity in the design of the RCTs included in this study, results supported improvement of systemic inflammation (hs-CRP) after periodontal treatment. Furthermore, RCTs were single centre [27,29] or single centre pilot studies [34]. Although single centre studies provide the flexibility of approach necessary for clinicians and scientists and an important source for new therapeutic ideas, they may be limited by difficulties in recruiting large numbers of participants. Another problem of such studies is the restrictive selection of studied patients that may hamper the generalization of findings.
About the 11 non-randomized prospective studies, only 4 of these included a control group [26,30,36,37]. The objectives of the latter was to evaluate the effect of periodontal treatment on fatal events in ESRD patients [30], and on systemic inflammation [26,36] or glomerular filtration rate [37] in patients with different stages of CKD undergoing conservative treatment. Despite the heterogeneity in the design of non-randomized prospective studies and therefore the difficulties to conclude on the influence of periodontal treatment on CKD, results are promising about impact of periodontal treatment on systemic inflammation and GFR.
The primary endpoint differed between studies; inflammation markers were the most frequently used. Measurement of CRP is obviously interesting owing to its association with cardiovascular disease and mortality [46], but periodontitis is an infectious disease that creates overall inflammation in active periods, including increase of CRP levels [6], and therefore improvement of inflammatory markers may not be sufficiently specific to CKD improvement. Furthermore, GFR is used to diagnose CKD and eGFR <60 ml/min/1.73 m 2 is associated with subsequent risk of all-cause and cardiovascular mortality, kidney failure, acute kidney injury, and CKD progression in the general population and in populations with increased risk for CVD [47]. However, this was the primary endpoint in only 2 studies. This endpoint should be measured in future studies.
In most studies, the efficacy of the purposed periodontal treatment was evaluated by measuring periodontal indices; this is a prerequisite to conclude on the influence of periodontal treatment on CKD status. However, in the included studies, the number of teeth or the capacity of chewing were not taken in account in the design of studies whereas the decrease of chewing ability will influence the diet of patients [48]. Moreover, periodontal treatment is able to prevent further tooth loss [49]. Not taking in account the number of teeth could be a bias regarding the fact that a liquid alimentation is a negative predictive risk in CKD or ESRD patients. A matching on this confounding factor can be implemented with the simple use of a questionnaire.
About the retrospectives studies, three [39][40][41] showed that ESRD patients receiving intensive periodontal treatment had a significantly lower risk of infections, of cardiovascular diseases and of mortality compared to those without periodontal disease. However, this could also lead to the conclusion that having a treated periodontal disease is better than no disease at all. This highlights a problem with retrospective studies for which it is practically impossible to identify and include patients who are underdiagnosed for periodontal disease.
The heterogeneity of design and protocols between studies does not allow for clear conclusions about the benefit of periodontal treatment in CKD and periodontitis patients in terms of systemic inflammation, GFR, or mortality; further methodologically robust RCTs are needed to demonstrate with a high level of evidence such potential benefit. It is of note that although there are studies that specifically investigated ESRD patients, the others did not distinguish patients on renal disease severity. Future RCTs should separate ESRD patients from those at other stages of CKD as the former are more fragile, often with haemodialysis, and are less likely to follow PTs and regular follow-up; studies including ESRD patients should assess specifically adapted therapies, e.g. prevention or oral hygiene instructions, which can be provided in haemodialysis centres. In addition, basic methodological aspects must be taken into account in order to minimize confounding bias, i.e. selection, attrition, performance, and detection bias. Randomization should include an adequate generation of allocation sequence associated with a clear concealment of allocation. When double-blinding cannot be obtained, a blinded assessment of the endpoints must be performed by a specific adjudication committee. The number of lost to follow-up must be minimized and handling of dropouts and missing data should be specified a priori in the study protocol. In order to avoid Type I Error Rate Inflation, dealing with multiplicity has to be also considered in the first versions of the protocol. Coordinated work and dialogue between nephrologist and periodontist seems obviously extremely important to set up for these future studies.
Periodontal treatment seems to improve CKD status, and results are encouraging especially for the reduction of systemic inflammation. However, further RCTs are needed to confirm these results and to specifically assess the influence of different types of periodontal treatment in CKD patients as well-documented for other systemic diseases such as diabetes [50,51].