Oral health in patients with end‐stage renal disease: A scoping review

Abstract Objectives In patients with end stage, renal disease a high rate of morbidity and mortality is present. Studies suggest that end stage renal disease may affect oral health. Therefore, the aim of this study was to perform a scoping review on periodontal disease, dental caries, xerostomia, and hyposalivation in end stage renal disease patients. Materials and methods A literature search (in PubMed and Embase.com) was performed up to September 29, 2020, in collaboration with a medical information specialist. Included outcome variables were the community periodontal index, probing pocket depth, gingival index, bleeding on probing, decayed‐missing‐filled‐teeth, carious‐absent‐obturated index, Xerostomia Inventory and the (un)stimulated whole salivary flow rate. Results Forty three out of 1293 studies were included in the final review comprising 7757 end stage renal disease patients. The average age was 58.3 ± 29.4 years. 28.2%–78.8% of patients reported xerostomia and the (un)stimulated salivary flow rates were significantly lower. Higher community periodontal index scores were measured in end stage renal disease patients. More decayed‐missing‐filled‐teeth were recorded, but no differences were found between groups. Conclusions Xerostomia and hyposalivation were highly prevalent in end stage renal disease patients. Patients have more deepened pockets, but an equal number of carious teeth compared to healthy controls.


| INTRODUCTION
The global prevalence of chronic kidney disease (CKD) including its most critical stage; end stage renal disease (ESRD), is estimated to be between 13.9% and 0.1%, respectively. Diabetes, hypertension and an older age are significant risk factors for developing CKD and ESRD (Hill et al., 2016). The disease is more common among women than men (Carrero, Hecking, Chesnaye, & Jager, 2018). The decline in kidney function causes waste products to accumulate inside the body (Brennan, Collett, Josland, & Brown, 2015;Webster, Nagler, Morton, & Masson, 2017) and causes symptoms like reduced mobility, lack of energy, reduced appetite, and sleeping disorders (Webster et al., 2017). Complications of CKD include fluid retention, anemia (Babitt & Lin, 2012;Bello et al., 2017), and it is an independent risk factor for cardiovascular disease and mortality (Matsushita et al., 2012). This risk rises with the progression of kidney dysfunction (Manjunath et al., 2003).
Individuals with a severe loss of kidney function (ESRD) may require renal replacement therapy when noninvasive measures no longer provide symptom relief (Glorieux & Tattersall, 2015). Currently, the best treatment option for renal replacement therapy is a kidney transplantation. Until a donor-kidney becomes available dialysis therapy is necessary.
Besides systematic complications from CKD and ESRD, oral health may be negatively affected by the disease itself, its treatment and its associated lifestyle alterations. Estimates are that oral diseases are present in almost 90% of dialysis patients (De Rossi & Glick, 1996). A diminished oral health in ESRD patients was frequently reported (Ruospo et al., 2014). Dry mouth is often present and may be associated with a fluid-restricted diet and hemodialysis drug therapy (Proctor, Kumar, Stein, Moles, & Porter, 2005). In the long-term, patients with a dry mouth are predisposed to develop more caries, periodontal disease, and mucosal lesions (Bossola & Tazza, 2012;Porter, Scully, & Hegarty, 2004). Moreover, oral symptoms, especially a lower salivary flow and a lower number of teeth, are related to a lower oral health related quality of life (Ruokonen et al., 2019). Therefore, keeping good oral health is of key importance for ESRD patients.
Recently, several studies concerning the oral health in ESRD patients were performed. Therefore, the aim of this scoping review is to update the available literature on periodontal disease, dental caries, xerostomia, and hyposalivation in ESRD patients.

A literature search was performed based on the Preferred
Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement (Moher, Liberati, Tetzlaff, & Altman, 2009).
Additionally, the Preferred Reporting Items for Systematic Reviews and Meta-analyses extension for Scoping Reviews (PRISMA-ScR) (Tricco et al., 2018) was used.
To identify all relevant publications, a systematic search in the bibliographic databases PubMed and Embase.com was conducted from inception to September 29, 2020, in collaboration with a medical information specialist. The following terms were used (including synonyms and closely related words) as index terms or free-text words: "Chronic renal insufficiency", "Kidney failure", "Renal dialysis", "Hemodialysis", "Periodontitis", "Xerostomia".
The references of the identified articles were searched for relevant publications. Duplicate articles were excluded. All languages were accepted. The full search strategies for all databases can be found in Supplementary Table S1.

| Selection process
Three reviewers (AL, LB and LH) independently screened the potentially relevant titles and abstracts for eligibility using the review manager Rayyan QCRI (Ouzzani, Hammady, Fedorowicz, & Elmagarmid, 2016). If necessary, the full text article was checked for the eligibility criteria. Differences in judgment were resolved through a consensus procedure. Studies were included if they met the following criteria: (a) Adult patients ≥18 years old with chronic kidney disease stage G5 (eGFR <15 ml/min/1.73 m 2 body surface area) with or without dialysis therapy (including patients waiting for a transplant); (b) studies on oral health including any of the following: periodontal disease, dental caries, xerostomia, or hyposalivation; (c) studies assessing the influence of renal insufficiency on oral health; (d) observational studies (cohort, case-control and cross-sectional studies); (e) written in English, Dutch or translated. We excluded studies if they were: (a) studies in which the type or severity of renal insufficiency was not specified; (b) studies in which patients were suffering from acute kidney injury or acute-on-chronic renal failure or in which patients were examined after receiving a renal transplant; (c) studies assessing the influence of oral health on renal insufficiency; (d) letters or comments on articles, study protocols, preliminary studies, pilot studies, case series (<4 patients) or case reports.

| Data assessment
The full text of the selected articles was obtained for further review.
Three reviewers (AL, LB and LH) independently evaluated the methodological quality of the full text papers using the Joanna Briggs Institute Critical Appraisal Checklist for Studies Reporting Prevalence Data (Munn, Sandeep, Lisy, Riitano, & Tufanaru, 2015), Supplementary   Table S2. It consists of nine questions regarding the possibility of bias at the study and outcome level. The checklist was mainly used to assess the overall body of evidence and validity of the results.
The relevant values of the periodontal variables (in view of periodontitis) were probing pocket depths >3 mm, corresponding with CPI scores of 3 (pocket depth 4-5 mm) and 4 (pocket depth ≥ 6 mm) and moderate to severe inflammation, indicated by GI scores of 2 (moderate) and 3 (severe) and sites with (immediate) bleeding on probing.
Results from individual studies were represented in tables. Means and SDs that were available for subgroups were recalculated for the whole group if applicable.
One study selected ESRD patients but did not mention whether they were on dialysis, and one selected ESRD patients that were not on dialysis. Thirty studies focused on hemodialysis, one focused on peritoneal dialysis, one compared patients on hemodialysis and peritoneal dialysis, and six studied ESRD patients, who were on either hemodialysis or peritoneal dialysis. Of these studies, seven considered whether the length of time spent on dialysis had any consequences on oral health and eight studies studied diabetic dialysis patients. Fifteen studies compared their subjects with a healthy control group, of which 12 studies used ageand/or gender-matched controls.

| Quality assessment
The results of the critical appraisal can be found under Supplementary   Table S2. No study did random probabilistic sampling in a pool of ESRD subjects. Loss to follow up (question 9) was only applicable to the longitudinal study. All studies scored well on the critical appraisal.
The majority of the studies had a cross-sectional design.

| Periodontal disease
Studies reported different indices related to periodontal health. The prevalence of CPI 3 in ESRD patients varied between 7.5% and 57.0% and of CPI 4 between 1.0% and 78.9% (Table 2). All subjects (both ESRD patients and healthy controls) showed signs of gingival inflammation.
No study found significantly deeper pockets in ESRD patients compared to healthy controls (Table 4) who did not observe an increase in pocket depth in dialysis patients after a 2-year follow-up (Bots et al., 2007).
The percentages BOP in ESRD patients ranged from 9.4% (low) to 63.9% (high). There was no significant difference in BOP between dialysis patients and healthy controls (Bots et al., 2006). The time spent on dialysis was not associated with higher BOP levels (Palmer et al., 2016;Sekiguchi et al., 2012). Bots et al. found a significant decrease in BOP levels of dialysis patients after 2 years (Bots et al., 2007). Schütz et al. described that 59.4% of ESRD patients was diagnosed with severe periodontitis (Schütz et al., 2020). One study reported the total surface area of inflamed periodontal tissue (PISA score) per patient (Križan Smojver et al., 2020).

| Caries
There was a huge spread in mean DMFT scores ranging from 1.4 (almost no carious teeth) to 26.0 (almost all teeth were carious)  (Sekiguchi et al., 2012), while three studies did not (Bots et al., 2006;Chuang et al., 2005;Jain et al., 2014). The study of Gavaldá et al. used the Carious, Absent and Obturated (CAO) Index, according to the World Health Organization (WHO) guidelines of 1987 (Gavaldá et al., 1999). Oliveira et al. reported that 82.7% of patients on hemodialysis had untreated dental caries (Oliveira et al., 2020). No significant differences were found when comparing the DMFT scores of hemodialysis patients to those of healthy controls.
Xerostomia was reported significantly more often in diabetic peritoneal dialysis patients compared to nondiabetic peritoneal dialysis patients (Eltas et al., 2012), but no difference was found between diabetic hemodialysis patients and nondiabetic hemodialysis patients (Murali et al., 2012;Swapna et al., 2013  The scores on the Xerostomia Inventory ranged from 28.3 to 34.1, indicating moderate to moderate high levels of xerostomia (Table 4). No association was found between the duration of dialysis and XI scores (Bots et al., 2004;Bots et al., 2007). Chuang et al.
The mean unstimulated whole salivary flow rate varied between 0.16 and 1.30 ml/min (Table 5). Two studies found a significantly lower UWSFR in hemodialysis patients compared to healthy controls (Kaushik et al., 2013;Kho et al., 1999). The prevalence of hyposalivation varied between 16.0% and 53.3%. The mean stimulated whole salivary flow rate varied between 0.42 and 3.80 ml/min (Table 5). Two studies described a lower SWSFR in hemodialysis patients compared to healthy controls (Gavaldá et al., 1999;Kaushik et al., 2013).

| DISCUSSION
Since the burden of oral symptoms in end stage renal disease patients may be high, the aim of this scoping review was to summarize the available literature on periodontal disease, dental caries, xerostomia, and hyposalivation in this patient group. Xerostomia and hyposalivation were highly prevalent in ESRD patients. Also, caries Dry mouth (xerostomia and hyposalivation) is highly prevalent in ESRD patients, and even though it is also present in the adult population (Jamieson & Thomson, 2020), it is more prevalent in ESRD patients compared to healthy controls. Dry mouth in ESRD patients may be caused by a fluid restricted diet, (multiple) medication use with dry mouth as side effect, the dialysis procedure itself, and/or salivary gland fibrosis and atrophy (Bossola & Tazza, 2012). Lack of saliva and dry mouth feeling may have several consequences for patients. They may lead to difficulty chewing, speaking and swallowing, taste alterations, halitosis, increased risk of oral infections, such as candidiasis, increased risk of (rapidly progressing) caries and periodontal disease, increased risk of fluid intake and interdialytic weight gain, and reduced quality of life (Bossola, 2019;de la Rosa García et al., 2006;Weisbord et al., 2005).
Diabetes mellitus was reported as a contributing factor for a dry mouth, patients with poor glycemic control experienced more oral dryness than patients with good glycemic control. High blood sugar levels lead to the excretion of large amounts of urine, which in turn leads to a decrease in intravascular fluid and hence an increase in oral dryness (Silveira Lessa et al., 2015). We found somewhat conflicting results when comparing diabetic and nondiabetic dialysis patients.
Diabetes mellitus is also associated with microvascular and macrovascular complications and is considered to be a risk factor for the development, progression, and severity of periodontitis (Verhulst, Loos, Gerdes, & Teeuw, 2019). Some studies compared diabetic versus nondiabetec ESRD patients. However, there were no significant differences between diabetic and nondiabetic ESRD patients regarding several periodontal parameters (Chuang et al., 2005;Murali et al., 2012;Naruishi et al., 2016;Swapna et al., 2013).
The total caries experience was mostly measured by the DMFT index. The variation in DMFT scores between studies was quite high.
However, mostly high DMFT scores were measured in both ESRD patients and healthy subjects. As the DMTF index can only get higher when age increases, the high scores may partly be explained by the higher age of the included patients. Results comparing ESRD patients and healthy controls were conflicting and no clear difference between the groups was visible. However, in dialysis patients there was some evidence for a higher caries prevalence in patients with concomitant diabetes mellitus (Chuang et al., 2005;Eltas et al., 2012;Swapna et al., 2013).
Besides xerostomia, hyposalivation, caries and periodontitis, and other oral complications or oral symptoms could be present in ESRD patients. For instance, edentulousness, mucosal disease, bad oral hygiene, mucosal sensitivity, oral pain, thirst, dysgeusia, or oral cancer may be more present than in healthy controls (Ruospo et al., 2014).
However, these symptoms were less studied and therefore not part of this review.
Differences in study design, number of included patients, outcome measurements and country of origin led to differences in outcome measurements. Smaller number of patients lowers the power of the study, while in large cohorts small differences may turn out statistically significant while they are not clinically relevant. Especially the described periodontal parameters differ between the studies, making a good comparison difficult. The quality of dental care varies greatly in the world. Also, costs of oral care and insurance policies differ between countries and they have an effect on the extent to what patients seek dental care. In this review studies from different parts of the world are included and they may partially explain differences between studies.
ESRD patients may be waiting for a kidney transplant. Potential transplant candidates should be free of inflammation before they can receive a transplant, in order to avoid infectious complications when on anti-inflammatory drugs after transplantation . Since periodontal inflammation and/or dental caries in ESRD patients are common, and low salivary flow may predispose to the rapid progression of these diseases later, a careful examination of the oral cavity and treatment of oral problems before transplantation may be part of the pretransplant procedure.
To conclude, xerostomia and hyposalivation were highly prevalent in ESRD patients. Also, caries and periodontal disease were present.
ERSD patients may have more deepened pockets, but not more carious teeth compared to healthy controls.