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00001665-201205000-0010800001665_2012_23_e214_silva_transplant_3article< 72_0_10_6 >Journal of Craniofacial Surgery© 2012 Mutaz B. Habal, MDVolume 23(3)May 2012p e214–e218Oral Lesions in Renal Transplant[Brief Clinical Studies]da Silva, Luiz Carlos Ferreira DDS, PhD, MSc*; de Almeida Freitas, Roseana DDS, PhD, MSc†; de Andrade, Manoel Pacheco Jr MD*; Piva, Marta Rabello DDS, PhD, MSc*; Martins-Filho, Paulo Ricardo Saquete DDS, MSc*; de Santana Santos, Thiago DDS, Msc‡From the *Federal University of Sergipe, Aracaju; †Federal University of Rio Grande do Norte, Natal; and ‡University of São Paulo, Ribeirão Preto, Brazil.Received August 18, 2011.Accepted for publication November 20, 2011.Address correspondence and reprint requests to Luiz Carlos Ferreira da Silva, DDS, PhD, MSc, Hospital Universitário, Departamento de Odontologia, Universidade Federal de Sergipe, Rua Cláudio Batista, s/n Bairro Sanatório, Aracaju, SE, Brazil CEP 49060-100; E-mail: lcsilva@ufs.brThe authors report no conflicts of interest.AbstractAbstract: To prevent rejection of kidney transplants, patients must be kept in immunosuppressive therapy for a long time, which includes the use of drugs such as cyclosporine, azathioprine, cyclophosphamide, and prednisone. The action of these drugs reduces the general immune response of transplant patients and thus increases their susceptibility to infections. Moreover, these drugs increase the potential of developing lesions. Therefore, oral hygiene in kidney transplant recipients contributes to maintenance of the transplanted organ and its function. Thus, an investigation of oral lesions could be counted as a notable work. The aim of this study was to investigate oral lesions in a group of 21 kidney transplant patients under immunosuppressive therapy attended during a 1-year period in the Nephrology Department of the Federal University of Sergipe, Brazil. Data related to sex, age, etiology of renal disease, types of renal transplant, time elapsed after transplantation, immunosuppressive treatment, use of concomitant agents, and presence of oral lesions were obtained. All patients received a kidney transplant from a living donor, and the mean posttransplantation follow-up time was 31.6 months; 71.5% used triple immunosuppressive therapy with cyclosporine A, azathioprine, and prednisone. Ten patients were also treated with calcium-channel blockers. Of the 21 transplant patients, 17 (81%) presented oral lesions. Gingival overgrowth was the most common alteration, followed by candidiasis and superficial ulcers. One case of spindle cell carcinoma of the lower lip was observed. Oral cavity can harbor a variety of manifestations related to renal transplantation under immunosuppressive therapy.Kidney transplantation is the treatment of choice for patients with irreversible renal failure, and it is associated with a 5-year survival rate in more than 60% of cases. To prevent rejection of kidney transplants, patients must be kept in immunosuppressive therapy for a long time, which includes the use of drugs such as cyclosporine, azathioprine, cyclophosphamide, and prednisone. The action of these drugs is complex and not yet fully understood, although it is known that this therapy reduces the general immune response of transplant patients and thus increases their susceptibility to infections.1 Therefore, oral hygiene in kidney transplant recipients contributes to maintenance of the transplanted organ and its function.2In addition, it has been well recognized that these patients are more susceptible to malignant tumors, with the oral cavity and associated structures an important target area.3 We investigated the presence of oral lesions in 21 renal transplant patients under immunosuppressive therapy. The knowledge of oral lesions due to immunosuppressive therapy in renal transplant patients is of paramount important to establish strategies in an attempt to improve quality of life in these patients.MATERIALS AND METHODSSample DesignAll patients assigned to this case series study were being treated at the Nephrology Department of the Federal University of Sergipe, Brazil. Kidney transplant patients at least 18 years old and under immunosuppressive therapy were included in this study.Clinical AssessmentIn a period of 1 year, a complete intraoral clinical examination was performed for all patients by the same examiner according to a set protocol, which included the use of standard dental office lighting and a dental mouth mirror. The patients were screened for the presence of pathologic manifestations. Biopsies were performed when necessary. After diagnosis, the manifestations were grouped in (1) hyperplastic lesions, (2) infections, (3) premalignant and malignant lesions, and (4) other lesions. Incidental lesions that were not considered to be associated with immunosuppressive therapy were excluded from this study. Details of sex, age, etiology of renal disease, types of renal transplant, posttransplantation period, immunosuppressive treatment, and use of concomitant agents were also collected. This survey was approved by the institution’s ethics committee.Data AnalysisCase series are descriptive studies of a small number of subjects having a particular condition or receiving a new therapy. In this study, we limited the analysis to the description of the variables such as proportions and means. Interpretations are summarized in the tables.RESULTSA total of 21 kidney transplant patients were examined, 14 men and 7 women, with a mean age of 36.9 years (range, 21–58 years). All patients received a kidney transplantation from a living donor, and the mean posttransplantation follow-up time was 31.6 months (range, 3–89 months); 71.5% used triple immunosuppressive therapy with cyclosporine A, azathioprine, and prednisone. Ten patients were also treated with calcium-channel blockers.Of the 21 transplant patients, 17 (81%) presented oral lesions. The cases of hyperplastic lesions, diagnosed as gingival overgrowth, were the most common manifestations, followed by infections and superficial ulcers. One case of spindle cell carcinoma of the lower lip was observed (Table 1; Figs. 1–4).TABLE 1 Distribution of Oral Lesions Among 21 Renal Transplantation PatientsFIGURE 1. Mild gingival overgrowth of the interdental papillae (A) and marginal gingiva (B).FIGURE 2. Pseudomembranous candidiasis in buccal mucosa (A) and the erythematous type in the palate (B).FIGURE 3. Infection by herpes simplex virus in the lip vermilion.FIGURE 4. Spindle cell carcinoma in the lower lip and actinic cheilitis in the upper lip.Regarding gingival overgrowth, it was observed that this condition occurred in 80% of the patients who used cyclosporine A in combination with calcium-channel blockers, in contrast with the 60% of the patients who did not use the 2 types of drugs. Fungal infections were more common than viral infections. The features of the cases in this series are summarized in Table 2.TABLE 2 Clinical Features of the 21 Kidney Transplantation Patients Under Immunosuppressive TherapyDISCUSSIONRenal transplant patients may exhibit a variety of oral lesions that appear to be related either directly to medication or arise as a consequence of drug-induced immunosuppression.3 Gingival overgrowth is one of the most prominent effects of therapy with cyclosporine A, and its incidence varies from 13% to 85%, depending on the evaluation criteria and methodology used.4 Others serious adverse effects of cyclosporine A include nephrotoxicity, hepatotoxicity, and hypertension. Calcium-channel blockers such as nifedipine and amlodipine have been used to mitigate the renal vasoconstriction caused by cyclosporine A and thus relieve hypertension.5 However, the concomitant use of both drugs has been shown to be associated with increased prevalence of gingival overgrowth compared with monotherapy with cyclosporine A,3,6 as observed in the current study. According to some authors,7,8 most cases of gingival overgrowth occur in areas of dental plaque, resulting in an increased number of inflammatory cells, degree of tissue vascularization, and deposition of intercellular matrix. In addition, genetic predisposition and pharmacokinetic variables appear to be significant in the expression of this condition.9In the current study, 13.1% of the lesions were diagnosed as superficial ulcers, a similar prevalence to that found by Greenberg and Cohen.10 In contrast, in a recent study performed by Lopez-Pintor et al,11 a low prevalence of ulcers was observed, affecting 2.2% of the patients. The lesions may be caused by epithelial cytotoxicity or as a secondary result of epithelial sloughing due to the use of drugs that prevent cell proliferation and repair.12 In rare circumstances, oral ulcers may be associated with cytomegalovirus (CMV) infection.13The immunosuppressive drugs, such as azathioprine, may also facilitate the establishment of infections by several microorganisms, among which stand out candidiasis and herpes simplex. In the current study, 2 cases of pseudomembranous candidiasis and 1 case of erythematous candidiasis were observed, with prevalence rates of 8.8% and 4.3%, respectively, similar to those found by King et al.14 The erythematous candidiasis in renal transplant patients must be differentiated from that caused by the use of ill-fitting dentures, because it is directly related to the degree of immunesuppression of the patient, similar to what happens in the infection by human immunodeficiency virus.Herpes simplex virus infection in renal transplant patients occurs between 50% and 75% of the cases and can be an important factor related to death.1 However, in the current study, 1 case of herpetic infection was observed, amounting to a prevalence of 4.3%. Possibly, this difference can be explained by the fact that we have examined patients in a single session, in contrast to the other studies that followed patients over the first year after transplantation. In addition, there is a greater likelihood in the patient who had the infection in the first 2 months after transplantation.3The development of Kaposi sarcoma (KS) in renal transplant patients and its association with other species of the Herpesviridae family, such as human herpesvirus 8 (HHV-8) and CMV (HHV-5), have also been studied.15–17 According to Farge et al,15 immunosuppression is classically considered as the main risk factor for KS, but the relative risk contributed by the patient’s geographic origin and by HHV-8 infection still has to be determined. The authors performed a retrospective and a prospective study among 30 kidney transplant recipients and observed that African and Middle East geographic origins, HHV-8 infection before and after kidney transplantation, and initial use of polyclonal antilymphocyte sera were independent risk factors for KS. The presence of HHV-8 antibodies before or after transplantation was highly predictive of the emergence of posttransplantation KS and conferred a 28-fold increased risk of the lesion. Kaposi sarcoma is 400 to 500 times more common among transplant patients than among the general population, afflicting 1 of 200 transplant patients in the United States. However, a small number of cases were related in the oral cavity. In a study performed by Margolius et al,16 with 989 renal transplant patients, 95 malignancies occurred in 75 patients; 5 (5%) of the 95 lesions were KS, of which only 1 case occurred in the oral cavity. Siegal et al reported a case of gingival KS in a human immunodeficiency virus–negative renal transplant patient that developed shortly after an acute infection with CMV.17a The lesion regressed after discontinuation of the cyclosporine therapy and the recovery from the acute CMV infection. In the current study, no case of KS was observed.According Lutz and Heemann,18 malignant tumors develop in 15% to 20% of graft recipients after 10 years and thus contribute substantially to the morbidity and mortality of these patients. According to Grulich et al,19 several factors may contribute to the increased incidence of malignancies in transplant patients, including chronic uremic status, cumulative exposure to immunosuppression, and certain drugs that can be carcinogenic through independent mechanisms or as a result of immunosuppression and viral infections. Malignancies can develop in 3 ways: de novo occurrence in the recipient, recurrence malignancy, or transmission of malignancy from the donor.18 Appropriate selection of transplantation candidates, pretransplantation and posttransplantation cancer surveillance and judicious evidence-based use of newer immunosuppressants may help reduce the incidence and improve the outcome of posttransplantation cancer.20Excluding skin cancers, squamous cell carcinomas make up most head and neck cancers in transplant recipients.21,22 In the lower lip, the incidence of spindle cell carcinoma in immunosuppressed renal-transplant recipients is considerably higher than in the normal population. In addition to immunosuppressive treatment, the most important risk factors for the development of lip cancer in these patients are exposure to sunlight and smoking habits.23 According to Preciado et al,22 high doses of immunosuppressive drugs, most notably prednisone, correlate significantly with advanced diagnosis and earlier death. In the current study, we found 1 case of spindle cell carcinoma of the lower lip in a 42-year-old fair-skinned man under use of immunosuppressive therapy with prednisone who had undergone kidney transplantation 5 years ago. The patient had a history of prolonged exposure to solar radiation and presented simultaneously another spindle cell carcinoma in the forehead skin and actinic cheilitis in the upper lip confirmed by the presence of solar elastosis in the histopathologic analysis. In kidney transplant recipients, screening before and after transplantation and an individualized choice of immunosuppression are thus mandatory.18 Patients should also be advised to avoid unprotected exposure to sunlight, to use appropriate sunscreens, and to stop smoking. In addition, the authors suggest that all lip ulcers that persist for more than 1 month, in patients under immunosuppressive therapy, should have a biopsy performed on.24 Moreover, the elimination of oral fungal lesions in kidney transplant recipients is highly recommended.2In summary, it could be concluded that the oral cavity can harbor a variety of manifestations related to renal transplantation, being necessary to establish a preventive oral care program aiming to improve the quality of life of these patients.REFERENCES1. Ariyawardana SP, Hay KD. Oral manifestations and dental management of immunocompromised patients. N Z Dent J 1999; 95: 89–97 [Medline Link] [Context Link]2. 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Int J Dermatol 2001; 40: 540–541 [Context Link]8. McGaw T, Lam S, Coates J. Cyclosporin-induced gingival overgrowth: correlation with dental plaque scores, gingivitis scores, and cyclosporin levels in serum and saliva. Oral Surg Oral Med Oral Pathol 1987; 64: 293–297 [Context Link]9. Seymour RA, Jacobs DJ. Cyclosporin and the gingival tissues. J Clin Periodontol 1992; 19: 1–11 [CrossRef] [Medline Link] [Context Link]10. Greenberg MS, Cohen G. Oral infection in immunosuppressed renal transplant patients. Oral Surg Oral Med Oral Pathol 1977; 43: 879–885 [CrossRef] [Medline Link] [Context Link]11. Lopez-Pintor RM, Hernandez G, de Arriba L, et al.. Oral ulcers during the course of cytomegalovirus infection in renal transplant recipients. Transplant Proc 2009; 41: 2419–2421 [Context Link]12. Ferguson CA, Whyman RA. Dental management of people with renal disease and renal transplants. N Z Dent J 1998; 94: 125–130 [Medline Link] [Context Link]13. 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