Over the past 50 years, organ transplantation has become a widely accepted and successful method of treatment around the world that has enabled hundreds of thousands of patients to receive the greatest therapeutic benefit (1). Owing to the noble act of donating organs (152 donors), the total of 363 organs were transplanted in Croatia in 2013, 208 renal transplants, 115 livers, 33 hearts and 7 pancreases (2).
Since all of the transplant recipients are under continuous immunosuppressive therapy for the prevention of chronic rejection, they are also more susceptible to the development of systemic complications and are at increased risk of orofacial diseases. Lesions in the oral cavity may arise as a direct result of immunosuppression or drug interactions (3, 4). Among the most common oral complications of immunosuppression are different viral infections caused by the herpes simplex virus, varicella zoster virus, cytomegalovirus and Epstein Barr virus associated with the development of hairy leukoplakia (5). An increased incidence of infection caused by the human papillomavirus, particularly in elderly patients with a renal transplant (6) and increased incidence of fungal infections caused by the fungus Candida species (7) has been shown, as well as a variety of bacterial infections (8). As a result of the interaction of cyclosporine A and calcium channel blockers, almost regularly in all patients receiving this combination of drugs, gingival hyperplasia appears (9). In patients with a renal transplant, lip and oral cancer are also described (10) and less frequently post-transplant lymphoproliferative disorders, oral ulceration and oral lichenoid reactions (11). In addition to the documented oral lesions, the emergence of new entities with characteristics of orofacial granulomatosis is described, especially in children with solid organ transplantation (12). Given the increase in the number of transplants in recent years, the possibility that the general dentist will encounter a transplant patient who requires special dental care because of the condition and treatment and because of possible oral lesions related to medication or immune response is greater (1, 2, 13). Therefore, the aim of our study was to investigate a) the prevalence and type of oral lesions, b) dental and oral hygiene status and salivation rate, c) oral lesions related to drugs and the time of renal transplantation, and d) the frequency of patient’s visits to the dentist in the post-transplant period.
SUBJECTS AND METHODS
The study was conducted in the period of two years (2011 and 2012), after approval by the Ethics Committee of the Clinical Hospital Center Zagreb and the Ethics Committee of the School of Dental Medicine, University of Zagreb. The study included 100 patients with renal transplant, and another 100 randomly selected control subjects who were neither organ recipients nor under immunosuppressive therapy.
The study protocol was explained to each patient, and after signing the informed consent, the patients were included in the study.
Transplant patient medical data included the period after the transplantation, the list of patient’s medications, and information about the last visit to the dentist. Clinical oral examination was performed in all transplant patients and controls (14). Data were recorded in a structured questionnaire.
Dental history included information about oral hygiene, the frequency of teeth brushing and flossing and use of mouth sustainers. Patients were asked about xerostomia symptoms and an affirmative response to at least one of the five following questions was used to confirm the subjective manifestations of xerostomia: “Does your mouth usually feel dry?”, “Does your mouth feel dry when eating a meal?”, “Do you have difficulty swallowing dry food?”, Do you sip liquids to aid in swallowing dry food?” and “Is the amount of saliva in your mouth too little most of the time, or do you not notice it?” (15). Along with subjective statements we applied the dental mirror adhesion test for more qualitative assessment of oral dryness. The test was performed by pressing a dental mirror on the dorsal side of the tongue (16).
In renal transplant patients, oral examination was performed during their regular control visit to the Department of Nephrology and Dialysis, University Hospital Centre Zagreb and the Department of Oral Medicine, School of Dental Medicine, University of Zagreb. The control group consisted of randomly selected patients who came for regular dental treatment at the Department of Endodontics and Restorative Dentistry, School of Dental Medicine, University of Zagreb. Oral and dental examinations were performed by the authors of this study M.G., A.G., K.G.
In all patients, clinical oral examination included the examination of oral mucosa, teeth and oral hygiene status which was carried out with a dental mirror and dental probe. Lighting was provided with exploratory examination light as recommended by WHO (17), while in dental office, the examination was performed in the dental chair. Inclusion criterion for all the patients was the minimum 18 years of age. Patients on dialysis were not included in the study.
Changes on the oral mucosa were classified according to morphological criteria in 5 groups (17): 1) erythema, 2) hyperkeratosis, 3) erosive-ulcerous lesions, 4) gingival hyperplasia, and 5) other. Under category "other" morphological lesions such as haemangioma, hairy tongue, geographic tongue, pigmentation and chemical and mechanical damage of oral mucosa were listed. Topography of oral lesions was observed and recorded according to the scheme of World Health Organization (17).
Gingival hyperplasia was classified in 3 stages according to Pernu’s modification of Angelopoulos’s and Goaz’s index (18) as follows:
grade 0 (S-0; normal gingiva), grade 1 (S-1; thickened marginal gingiva that covers one third of the crown), grade 2 (S-2; increased the marginal gingiva that covers half of the crown), grade 3 (S-3; a significant increase of the marginal gingiva which covers more than half of the tooth crown and the surrounding retaining gum).
Dental status was assessed by DMFT index, not including the third molars (19).
The degree of oral hygiene was determined according to the Silness-Löe plaque index (20), in all subjects except 13 patients with complete dentures. The measurement was based on recording both the soft debris and mineralized deposits on the teeth 16, 12, 24 in the upper jaw and 36, 32, 44 in the lower jaw. Missing teeth were not substituted. Each of the four surfaces of the teeth (buccal, lingual, mesial, distal) was given a score from 0-3:
1-A film of plaque adhering to the free gingival margin and adjacent area of the tooth. The plaque may be seen in situ only after application of disclosing solution or by using the probe on the tooth surface,
2-Moderate accumulation of soft deposits within the gingival pocket, or the tooth and gingival margin which can be seen with the unaided eye,
3-Abundance of soft matter within the gingival pocket and/or on the tooth and gingival margin.
The scores from the four areas of the tooth were added and divided by four in order to obtain the plaque index for the tooth. The index for the patient was obtained by summing the indices for all six teeth and dividing by six (19).
Lesions of the oral mucosa were photographically documented, and subjects were referred to the Department of Oral Medicine, School of Dental Medicine, University of Zagreb for further diagnostics and treatment.
All subjects were given the instructions on adequate oral hygiene.
The data were organized into files (Microsoft Excel, Microsoft Inc. U.S.) and statistically analyzed by using MedCalc V.11 program (MedCalc Software, Mariakerke, Belgium). To test the differences between continuous variables, t-test for independent samples was used, while the significance of the differences of categorical variables was tested by using chi-square test (χ2 test). Mann Whitney U test for independent samples was used for comparison of categorical variables with more categories. Correlations between individual variables were determined by Spearman correlation coefficient. Level of significance was determined at p <0.05.
Out of 100 renal transplant patients, 62% were women and 38% were men (mean age 52.48 ± 13.65; age range 18-74). Out of 100 control patients, 48% were women and 52% men (mean age 49.9 ± 13.47; age range 24-85).
Lesions on the oral mucosa
Renal transplant patients have a greater number of oral lesions (31%) than the controls (12%) (χ2 test, p=0.0019). Lesions were more frequently found in women (20/62) than in men (11/38). The average age of patients with oral lesions was 49.42 ± 15.16, in comparison to patients with no oral lesions 53.85 ± 12.79 (p>0.05). The distribution of oral lesions in renal transplant patients and the control group is shown in Table 1.
|Renal transplant group||Control group|
The most common lesion was mucosal erythema, and the least frequent were erosive-ulcerous lesions. Oral lesions appeared most frequently within two years after transplantation (Figure 1).
Gingival hyperplasia was found in only five renal transplant patients (four men and one woman), mostly in younger patients (the average age was 38.8 years) and with higher severity in women (grade 3) than in men (grade 2 and 1, respectively).
The occurrence of gingival hyperplasia was associated with the number and type of the drug (Table 2).
|SEX||TACROLIMUS||MYCOPHENOLATE MOFETIL||CYCLOSPORINE A||VALPROIC ACID||CALCIUM|
The most commonly used drugs in patients with renal transplant were corticosteroids (88%), mycophenolate mofetil (84%), cyclosporine A (75%) and calcium channel blockers (52%) (Table 3). Out of the 75 patients who were using cyclosporine A, 43 patients were additionally taking calcium channel blockers.
According to the topography of the WHO (17), the most common location of gingival hyperplasia was the marginal gingiva in the upper and lower anterior teeth, in the region of 31, 32, 37, 38.
The subjective feeling of oral dryness was present in 33% of renal transplant patients and 13% of controls (χ2 test, p=0.001). There was no significant correlation of oral dryness with age, sex, oral lesions or to any drug used by the renal transplant patient.
The average DMFT (decayed, missed, filled teeth) index of the patients with renal transplant was 14.75 ± 6.91, in comparison to control group 17.17 ± 6.23 and the difference was statistically significant (Mann-Whitney U test, p=0.0073).
The renal transplant female patients’ DMFT index was 16.29 ± 7.41, and in male patients 13.81 ± 6.47, without significant difference. There was no correlation of DMFT index with the time elapsed since transplantation (correlation coefficient r= - 0.2) nor with the patients' age (correlation coefficient r= 0.04).
Patients with renal transplant had the plaque index ranging from 0.6 to 1.9 (average 1.02 ± 0.27) and this finding was significantly different from the control group (0.6-1.4; average 1.11 ± 0.17) (Mann-Whitney U test, p=0.0001). No significant correlation was found between DMFT index and plaque index in the patients with renal transplant (correlation coefficient r= 0.126). Significant difference was found in the use of additional sustainers for oral hygiene between renal transplant patients (24%) and controls (62%) (χ2 test, p<0.0001). Only 48% of renal transplant patients have visited a dentist after the transplantation, and the average period was 79 months (Figure 2).
The Ministry of Health of Croatia recognizes the transplant program as one of its strategic goals, and in all health care reform implementation measures, treats it as a program of special national interest. As a full member of the European Union, in 2013 Croatia ensured the implementation of quality and safety standards of organs intended for transplantation described in the Directive 2010/45/EU of the European Parliament and of the Council on standards of quality and safety of human organs intended for transplantation (2).
Although the first organ transplant in Croatia was performed back in 1971, only after the year 2000, a continuous increase (the number of donors per million inhabitants) from 2.7 to 32 was recorded (1, 2). For the fourth time in a row, Croatia has been pointed out as the leading country in the world in organ donation and transplantation. According to internationally adopted key indicators of transplant program success, in 2013 Croatia was the first in the world in the number of renal transplants from deceased donors (47.7 per million people) and the second in the world in the number of actual organ donors (35 per million people) (2).
Renal transplant patients have an increased risk of developing oral lesions due to long-term immunosuppressive therapy. The most commonly described lesion in the literature is gingival hyperplasia while the data for other lesions are scarce and contradictory (5, 9, 21-23).
The results of our study showed that renal transplant patients had significantly more oral lesions (31%) than the controls (12%), which is in line with studies by other authors (3, 5, 15). However, unlike the study by de la Rosa et al. (9) in which the prevalence of oral lesions was 60%, in our patients, as in the study by López-Pintor RM et al. (15), it was almost two times smaller.
Time after renal transplantation is the time that has elapsed since the organ transplantation and in which the patient is under the influence of immunosuppressive therapy. It was from 1 to 301 months. The median time elapsed after the transplantation in our patients was 60 months (average value of 60.05 ± 66.61 months), as in the study by López-Pintor RM et al. (15), while in the study by de la Rosa et al. (9) it was 10 months. The reason for a more frequent occurrence of lesions in a shorter period after transplantation is the high doses of immunosuppressive therapy in the first months after transplantation (15). The period after transplantation was shorter in men (57.81 ± 66.69; 1-301) than in women (63.71 ± 67.36; 1-270) (p>0.05).
The most frequent oral lesions in our patients were erythematous changes (13%). In 4% it pointed to denture stomatitis (Newton 1 and Newton 2) with respect to topography, wearing upper dentures and due to inadequate oral hygiene. These patients continued treatment at the Department of Oral Medicine, School of Dental Medicine. The remaining 9% of erythematous changes pointed to marginal gingivitis.
Hyperkeratotic lesions were found in 9% of renal transplant patients. The most common clinical picture consisted of discrete changes on the buccal mucosa (regions 19 and 20 according to the WHO topography), whereas the two patients had clinical picture of oral lichen planus. In the study by López-Pintor RM et al., lichen planus was found in 0.6% (15) and in the study by Al-Mohaya M. et al. in 3.4% of cases respectively (5), while in the study by Dirschnabel AJ et al., hyperkeratotic changes and lichen planus were not found (3).
Gingival hyperplasia was found in 5% of our patients. According to the literature, the prevalence of gingival hyperplasia has a wide range. Authors Rojas G et al. noted this change in 10% (4), Sahebjamee-M et al. in 7% (24) and Dirschnabel AJ et al. in 15.2% of the cases (3). Other studies show a higher prevalence of up to 70% of cases (5). According to most authors, the occurrence of gingival hyperplasia was associated with three drug classes: immunosuppressive agents, calcium channel blockers and anticonvulsants (5, 24-26). Calcium channel blockers are often used in combination with immunosuppressive agents to reduce their nephrotoxicity (27). Combination therapy of cyclosporine A and calcium channel blockers showed a significantly higher incidence of gingival hyperplasia than when cyclosporine A is used alone (5, 24). In our study, 75% of patients were using cyclosporine A. In 57.3%, cyclosporine A was administered in combination with calcium channel blockers. Higher prevalence of gingival hyperplasia was observed in the combination of drugs cyclosporine A with amlodipine than in nifedipine with cyclosporine A (28).
Valproic acid as an anticonvulsant in the rare cases in adult patients causes gingival hyperplasia, and in children there were only a few documented cases (25). In our study, an 18-year old female patient who used cyclosporine A in combination with anticonvulsants (valproic acid and clonazepam) and the calcium channel blocker had severe gingival hyperplasia. All three groups of drugs that cause hyperplasia were used in our patients, which can be associated with the greatest intensity of those changes. Given that this is just one case, this relationship should be tested on a larger sample.
Studies show that the prevalence of gingival hyperplasia is three times more common in men (4, 29) compared to women as revealed in our study (4 males: 1 female) as well as in younger age groups (9, 25). This can be explained by a stronger inflammatory response, poor oral hygiene and hormonal imbalance in renal transplant patients (26). In our study there was a significant difference (t-test, p=0.02) between the average age of patients with hyperplasia (38.8 years) and without (53.2 years). According to the literature, gingival hyperplasia, mostly affects the upper and lower anterior teeth (9), which is consistent with our findings. Of particular importance in these patients is regular control of dental plaque and calculus (30).
Erosive-ulcerous lesions (aphthous ulcers), were noted in 3% of patients, while López-Pintor RM et al. found ulcerous lesions in 2.2% of cases (15). One of the causative factors for oral lesions after transplantation is immunosuppressive drug application protocol that is specific to each hospital center (24). The most commonly used immunosuppressive agent in our study was mycophenolate mofetil (84%).
Patients with renal transplant had the average DMFT index of 14.75 ± 6.91, which is almost identical to the findings of Rojas G et al. (4).
With regard to gender, a higher average value of DMFT index was noted in female patients unlike Rojas G et al. where a higher DMFT index was found in male patients (4). DMFT score in our study should be interpreted with caution while the assessment of DMFT index was done without a radiograph. It is possible that DMFT index would be much higher.
One third of our patients had a subjective feeling of oral dryness, whereas in the study of López- Pintor RM et al. it was recorded in only 1.4% of cases (15). The reduced amount of saliva as a side effect of antihypertensive drugs is a risk factor for the development of various infections in oral cavity (24).
According to the obtained average values of plaque index, oral hygiene in most of our patients was unsatisfactory, while in the study by de la Rosa Garcia et al. (9) and Rojas G et al. (4) in most patients, the oral hygiene was satisfactory.
To our knowledge, there are scarce data from the literature about the patients' frequency of visiting their dentists after organ transplantation. Our results have shown that only 48% of our patients visited a dentist after their transplantation in the period of 1-301 months with an average of 79 months.
Due to immunosuppression, a subjective feeling of oral dryness and poor oral hygiene, the patients have an increased risk of oral lesions (31). The obtained results are worrying and suggest the necessity of dentists' involvement in post-transplant medical team caring for patients with organ transplant. During the post-transplant period daily use of antiseptic solutions as well as regular visits to a dentist and antibiotic prophylaxis during the performance of invasive procedures are of great importance (31).
In conclusion, renal transplant recipients had more oral lesions which occurred within two years after the transplantation.
The most common were erythematous lesions; less frequent were keratotic changes, gingival hyperplasia and erosive-ulcerous lesions.
Gingival hyperplasia is directly associated with the type of drug taken by the patient.
The average DMFT index was significantly lower in patients with renal transplant than in the control group and its association with the time after the transplantation was not found.
Oral dryness was reported in one third of the patients with renal transplant.
In general, oral hygiene was unsatisfactory in all patients because patients used far less additional sustainers for oral hygiene (dental floss and products for dental rinsing) compared to the control group.
Most patients with renal transplant did not visit their dentist after the transplantation. In order to prevent the occurrence of complications and organ rejection in post-transplant period, along with monitoring general condition of the patient, it is equally important to detect and identify oral lesions early, which can point to possible complications of pharmacological treatment or the occurrence of graft versus host disease (GVHD), and improve quality of life in these patients. Therefore, in timely detection and treatment of oral lesions, a crucial role is played by the doctor of dental medicine (13).