Saudi Journal of Kidney Diseases and Transplantation

: 2009  |  Volume : 20  |  Issue : 1  |  Page : 20--29

Oral lesions in Saudi renal transplant patients

Maha Ali Al-Mohaya1, Azmi Mohammad-Ghaleb Darwazeh2, Salih Bin-Salih3, Waleed Al-Khudair4,  
1 Oral Medicine Clinic, Riyadh Armed Forces Hospital, Riyadh, Saudi Arabia
2 Department of Oral Medicine and Surgery, Jordan University of Science and Technology, Irbid, Jordan
3 Department of Medicine King Abdulaziz Medical City, Riyadh, Saudi Arabia
4 Department of Surgery, King Abdulaziz Medical City, Riyadh, Saudi Arabia

Correspondence Address:
Maha Ali Al-Mohaya
Consultant of Oral Medicine, Riyadh Armed Forces Hospital, P.O. Box 7897, Riyadh 11159
Saudi Arabia


Renal transplantation has evolved as the best treatment option for patients with end­stage renal disease. Different oral problems arise in these patients, either as a direct consequence of drug-induced immunosuppression or pharmacokinetics. To determine the prevalence of intra-oral lesions in a group of medically stable Saudi renal transplant patients (RTP) and to identify possible risk factors, in comparison with age and sex-matched healthy control subjects (HCS), we studied 58 RTP and 52 HCS. All subjects had a thorough oral examination and oral lesions were diagnosed according to the clinically accepted criteria. Gingival overgrowth (GO), erythematous candidiasis (EC) and hairy leukoplakia (HL) were diagnosed in RTP with prevalence of 74.1%, 15.5%, and 8.6%, respectively. The severity of the gingival overgrowth significantly correlated with the use of cyclosporine and nifedipine combination therapy, serum cyclosporine, and serum creatinine level. In conclusions, the finding of our study strongly propose that RTP should undergo routine and regular comprehensive oral examination, and any suspicious lesion must be investigate and treated.

How to cite this article:
Al-Mohaya MA, Darwazeh AM, Bin-Salih S, Al-Khudair W. Oral lesions in Saudi renal transplant patients.Saudi J Kidney Dis Transpl 2009;20:20-29

How to cite this URL:
Al-Mohaya MA, Darwazeh AM, Bin-Salih S, Al-Khudair W. Oral lesions in Saudi renal transplant patients. Saudi J Kidney Dis Transpl [serial online] 2009 [cited 2021 Jan 24 ];20:20-29
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Full Text


Renal transplantation has evolved as the best treatment option for patients with end-stage re­nal disease. During the last two decades, a sig­nificant progress has been achieved in graft and patient survival after renal transplantation. In part, this was attributed to improved surgical and tissue matching techniques, and to advan­ces in the anti-rejection drug therapy. [1],[2] The in­crease in the number and life expectancy of renal transplant patients (RTP) has an impact on oral and dental health services. Different oral and dental problems arise in these patients, most of which develop as a direct consequence of drug-induced immunosuppression or phar­macokinetics. [3],[4],[5]

Gingival overgrowth (GO) is a well recog­nized side effect of cyclosporine and calcium channel blockers, [6],[7] and both drugs are exten­sively used by RTP. The prevalence of GO among RTP receiving both cyclosporine and calcium channel blocker is believed to be grea­ter than in those receiving only cyclosporine. [8],[9],[10]

Amongst the different types of severe sys­temic infections following renal transplantation are those caused by fungi which carry a high mortality rate. [11],[12] Oral candidiasis in RTP has been rarely studied in comparison with other immunosuppressed patients such as those with HIV/AIDS. [13]

Due to prolonged immunosuppression, RTP are expected to be more liable to oral candidiasis compared with the immunocompetant subjects, but data in this regard are limited. [14]

Hairy leukoplakia (HL) was first described in 1984, and at that time it appeared to be limited to HIV seropositive patients. [15] Subsequent case reports have confirmed that this lesion occurs also in immunosuppressed HIV seronegative patients; [16],[17] however, studies on its prevalence in RTP are sparse. [3],[10]

Prevalence of oral lesions in the Saudi renal transplant population is largely unknown. There­fore, the aim of this study was to determine the prevalence of intra-oral lesions in a group of medically stable RTP, and to identify possible risk factors that may be associated with the development of these lesions, in comparison with age and sex-matched healthy control sub­jects (HCS).

 Patients and Methods

Fifty eight consecutive RTP, who had success­ful kidney transplant for at least 6 months, were recruited from the out-patient Renal Transplant Clinic at King Abdulaziz Medical City (KAMC). The control subjects constituted of 52 appa­rently healthy, age and sex-matched individuals and were recruited from the out-patient clinic at the College of Dentistry, King Saud University, Riyadh, Saudi Arabia. All control subjects were attending for routine dental treatment. Partici­pants were asked to sign an informed consent form which was approved by the local ethical committee.

The demographic data for each subject were recorded [Table 1]. Thorough oral and peri-oral examination was performed by the principal investigator (MAM). Oral lesions, when pre­sent, were diagnosed according to the history and the clinically accepted criteria. [18] Lesions with doubtful clinical diagnosis were biopsied. Criteria for diagnosis of oral lesions were as follows:

Gingival overgrowth (GO)

GO was diagnosed and scored according to Angelopoulos and Goaz. [19] Score 0: no GO [Figure 1]; Score 1: mild GO covering only the gingival one third of the tooth crown or less [Figure 2]; Score 2: moderated GO extending up to the middle of the crown [Figure 3]; Score 3: severe GO covering more than one half of the crown [Figure 4].

Hairy leukoplakia (HL)

The diagnosis of HL was made according to the criteria proposed by Ecclearinghouse. [20] An asymptomatic whitish gray lesion on the lateral margins of the tongue which is not removable and may exhibit vertical corrugation was diagnosed clinically as HL [Figure 5].

Oral candidiasis

Erythematous candidiasis (EC) was diagnosed according to the Ecclearinghouse [20] presumptive criteria as red areas located on the dorsum of the tongue or palate [Figure 6]. The clinical diagnosis was confirmed by microscopic de­monstration of candidal hyphae or blastospores in the smear and by positive growth of Candida colonies from swabs collected from clinically infected area and cultured on Sabouraud's agar plates. Candida species were identified using serum germ tube formation test and the com­mercially available yeast identification system API 20C AUX [21] (bioMerieux, Marcyl, Etiole, France).

Other intra-oral lesions were diagnosed accor­ding to the criteria described by Pindborg. [18]

Blood investigations

Blood investigations for RTP included blood urea nitrogen (BUN) levels, serum creatinine level, serum cyclosporine levels, and fasting blood glucose levels.


A total of 58 RTP (36 male and 22 female) and 52 HCS (34 male and 18 female) parti­cipated in the study. The mean age of RTP was 39.2 years (SD 12.8) ranging from 16 to 62 years, and of the HCS 37.1 years (SD 11.6) ranging from 16 to 60 years. The mean duration of transplant was 51.6 months (SD 31.9) ran­ging from 7 to 125 months. The source of renal transplant was cadaver in 39 (67.2%) patients, living non-related donor in 10 (17.2%) and living related donor in 9 (15.5%) RTP. None of the subjects was fully edentulous or using re­movable dentures. The RTP (except two pa­tients) were all on combination of immuno­suppressant agents. All RTP were taking the prednisolone, while 56 (96.6%) were on cy­closporine and 37 (63.8%) were on calcium channel blockers.

A total of 97 oral lesions or conditions were diagnosed in RTP compared to 38 lesions diag­nosed in HCS. [Table 2] shows the oral findings in both groups.

GO was the most frequently encountered le­sion in RTP where it was diagnosed in 74.1% of the patients, while none of the HCS had cli­nically evident GO (p= 0.000). Forty-one (95.3%) patients with GO were on cyclosporine, while 32 (74.4%) were on calcium channel blocker (either nifedipine or amlodipine). The preva­lence of GO among RTP who were medicated by both cyclosporine and calcium channel blo­cker (30/35 cases; 85.7%) was significantly hig­her (p= 0.006) than those who were on cyclos­porine alone (11/21(52.4%) cases).

All cases of RTP with severe GO were on combination of cyclosporine and calcium cha­nnel blockers. A total of six out of nine (66.7%) patients with moderate GO were on both medi­cations. On the other hand, only 2/9 (22.2%) patients who were on cyclosporine alone had moderate GO, while none had severe GO [Table 3]. No significant difference was detected bet­ween RTP with GO and those without GO in respect to age, gender, teeth brushing, Miswak use, smoking, dental status or duration of transplantation.

The statistical analysis showed no significant difference in the mean values of the blood investigations among RTP with and without GO except for serum cyclosporine level, which was significantly higher in patients with GO (mean 180± 55 ng/mL) compared with those without GO (mean 140 ± 40.4 ng/mL, p= 0.01) [Table 4].

One way ANOVA test has shown that RTP with severe GO had significantly higher mean of serum creatinine level than those with mild GO (194 v.s. 141 µmol/L, p= 0.01). Similarly, the mean fasting blood glucose levels were signi­ficantly higher in RTP with severe GO than in those without GO (7.3 v.s. 5 mmol/L, p= 0.03).

The second most frequently diagnosed oral le­sion in RTP was erythematous candidiasis (EC), which was diagnosed in 9 (15.5%) RTP, while Candida-associated angular cheilitis was diag­nosed in only one (1.7%) patient who had con­comitantly EC. C. albicans was isolated from five lesions (55.6%), while C. dubliniesis and C. famata each was isolated from two lesions (22.2%). None of the HCS had oral candidiasis. The prevalence of EC in RTP was significantly higher than in HCS (p= 0.002). Seven (77.8%) cases of EC were located on the dorsum of the tongue, while the remaining 2 (22.2%) cases were on the dorsum of the tongue as well as on the hard palate. The prevalence of EC was not related to age, gender, smoking, teeth brushing or duration of transplantation. Eight out of 33 (24.2%) RTP who were not using Miswak have shown clinical and microbilogical evidence of EC, and this was significantly higher than 1/25 (4.0%) of RTP who were using Miswak and developed EC (p= 0.04) [Table 5].

HL was diagnosed in 5 (8.6%) RTP, but was not observed in any HCS (p= 0.04). All lesions were present bilaterally on the lateral border of the tongue. No significant difference could be detected in the mean values of blood inves­tigations between RTP with HL and those with­out. Due to small number of patients with HL, no attempt was made to investigate the possible correlation with other variables such as medi­cations, age, and gender.


It is generally believed that RTP exhibit an increased prevalence of oral lesions that could be related either to the patient's medications or to their immunosuppressive state. However, with exception of GO, little is known about the prevalence of intra-oral lesions in RTP. [3],[5]

The prevalence of clinically evident GO among RTP of this study (74.1%) is within the range of 25%-81% of drug-induced GO previously re­ported by other studies, [3],[6],[8],[9],[22],[2]3,[24],[25] but higher than 22% reported in RTP by KING et al. [10] The wide range in the reported prevalence of drug­induced GO in RTP could be related to intrinsic variations in population samples such as genetic differences, standards of oral hygiene, the dose and duration of treatment and the criteria used to quantify the gingival enlargement. [26],[27]

The pathogenesis of the drug-induced GO is still a subject of investigation. The results of recent studies have indicated that cyclosporine affects signaling molecules in gingival fibro­blasts inducing an increase in AP-1, IL-6, and TGF-beta1 activity, which all increase the ex­pression of fibrinogenic molecules and promote GO. [28],[29] Stereological studies have shown that cyclosporine-induced GO represent altered com­position of gingival tissue characterized by in­creased thickness of epithelium, blood vessels, and non-collagenous matrix in the connective tissue. [30],[31] In addition, the suppression of T cell function in the gingival tissues by cyclosporine therapy can result in an increase of human papi­llomavirus infection, adding to the proliferative activity of cyclosporine. [32]

The data from this study have shown that RTP on a combination of therapy (cyclosporine and calcium channel blocker) had remarkably hig­her incidence and severity of GO when com­pared with those who were on cyclosporine alone, which was observed by others. [33],[34],[35] How­ever, the reasons are still not precisely deter­mined. A common pharmacodynamic feature of both drugs is their action on calcium hemo­stasis. Calcium channel blockers are calcium antagonists, and cyclosporine is known to lower the cytosolic free calcium. The synthesis and release of collagenases and other metallopro­teinases from gingival fibroblasts are calcium­dependent processes. Consequently, the intake of these drugs may lead to an impairment of collagenase synthesis and/or release, which may result in impaired collagenolysis. [30] The imba­lance between collagen production and break­down may be one of the mechanism(s) that may contribute to the development of GO in RTP. Theoretically, the combined inhibitory effects of both drugs on calcium-dependent collage­nase production may explain the qualitative and quantitative increase in gingival overgrowth observed in patients on combination of therapy. Flynn et al [36] have demonstrated that therapeutic combination of cyclosporine A and nifedipine could induce gingival edema synergistically secondary to increased sulfated-glycosamino­glycan (sGAG) synthesis by gingival fibroblasts.

Unfortunately, we were unable to evaluate the prevalence of GO among RTP who were taking calcium channel blocker alone due to very few number of patients taking this medication only (two patients). However, the relationship between drug pharmacokinetic variables and the preva­lence and severity of GO remains a matter of debate. Some studies suggest that a serum threshold concentration of cyclosporine is nece­ssary to induce gingival changes. [23],[24],[25],[26],[27]

The present study found that the mean con­centration of serum cyclosporine among RTP with GO was significantly higher than that in patients without GO. Recent studies have shown that the conversion of RTP medicated with cy­closporine to other immunosuppressive agents such as tacrolimus resulted in resolution or im­provement of GO. [37],[38] Additionally, we showed that RTP with severe GO had higher level of serum creatinine than those with mild GO. It is well known that elevation of serum creatinine concentration is an indicator of renal function impairment. Such elevation might be predis­posed by cyclosporine-induced nephrotoxicity. [39]

It is widely accepted that hyperglycemia is associated with biological alterations, which predispose to periodontal disease. [40] The present study has shown that blood glucose concen­tration in RTP with severe GO was significantly higher than that in patients without GO. Whe­ther higher blood glucose level in RTP acts as a co-factor contributing to the development or severity of GO in those patients needs further study.

Few case reports have documented malignant changes in drug-induced GO. [41],[42],[43] Therefore, oral health care providers dealing with RTP should be aware of this possibility and any suspicious lesion should be referred for histopathologic examination.

Oral candidiasis has been described in anec­dotal reports of RTP. [3],[10],[44] However, with ex­ception of few studies, [3],[10],[14] the prevalence of oral candidiasis in RTP remains to be deter­mined. In our study patients, EC was diagnosed in 15.5% of the patients, while none of the con­trol subjects had oral candidal infection. How­ever, no correlation could be detected between EC and age, gender, or smoking habit. More­over, the development of EC was not related to lack of oral hygiene practice in term of teeth brushing, which may suggest that oral candidia­sis was related mainly to immunosuppressive agents per se than any other factor. Our obser­vation that RTP who used Miswak as an oral hygiene tool had significantly lower prevalence of oral candidiasis may suggest an antifungal effect of Miswak, which has been demonstrated by some recent in vitro studies. [4]5,[46],[47]

Over the past two decades, several reports des­cribed fungal infections in immunocompromised patients, such as organ transplant patients, caused by Candida species other than albicans. [48],[49] Among our RTP, C. famata and C. dubliniesis were responsible for infection in 44.5% of the cases.

It is strongly believed that HL is associated with the presence of Epstein-Barr virus (EBV). [50] The prevalence of HL in HIV-infected patients ranges between 9% and 20% (51-54%). King et al [10] reported HL in 8.6% of RTP, which is not far away from 11.3% among our RTP. This finding supports the view that HL is not spe­cific to HIV infection but is a general mani­festation of immunosuppression.

The emergence of HL in HIV-infected patients is regarded as a marker for progression to AIDS. [51],[52],[53],[54],[55] The clinical significance of HL in RTP is difficult to interpret at this stage, but may be regarded as a marker of a significant overimmunosuppression.

It is well known that immunosuppressive the­rapy increases the risk of malignancy. [56],[57] Des­pite the fact that RTP are usually maintained on long-term powerful immunosuppressive therapy, the incidence of intra-oral malignancy appears low. As RTP survive longer, we may witness an increase in the incidence of intra-oral malig­nancy in patients on long-term immunosuppre­ssive therapy. Nevertheless, kidney transplant recipients are at high risk to develop other malignancies such as Kaposi's sarcoma, cancer of the uterine cervix, gastric cancer, basal cell carcinoma and non-Hodgkin's lymphoma. [58] None of these lesions were encountered among our study patients, possibly due to the relatively small sample size.

The other intra-oral lesions observed among RTP in this study were not believed to be associated either with renal transplantation or immunosuppression. In addition, their prevalence was not significantly different from that in HCS.

We conclude that the findings of the present study suggest RTP should undergo routine and regular comprehensive oral examination, and any suspicious lesion must be investigated and treated. In addition, RTP should be routinely screened for oral candidiasis, and identified le­sions treated with appropriate antifungal the­rapy. Strict oral hygiene and care are empha­sized in RTP.


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