(1) Maestría en Odontología, Departamento de Atención a la Salud. Universidad Autónoma Metropolitana Xochimilco, Ciudad de México
(2) MD, Nefrólogo. Servicio de Nefrología, Hospital General de Zona # 1, Instituto Mexicano del Seguro Social, San Luis Potosí, SLP, México
(3) Doctora en Odontología, Departamento de Atención a la Salud. Universidad Autónoma Metropolitana Xochimilco, Ciudad de México
(4) Dietista. Servicio de Nefrología, Hospital General de Zona # 1, Instituto Mexicano del Seguro Social, San Luis Potosí, SLP, México

Address:
Estela de la Rosa García
Cerro de la Estrella 117-401
Col. Campestre Churubusco
04200 México DF.
Teléfono (52) 55 5544-2848 Fax (52) 55 5483-7218
E-mail : EsteladelaRosa1@aol.com
amondragonpadilla@msn.com

Received: 16-07-2004  Accepted: 4-02-2005

INTRODUCCIÓN

Kidney transplant (KT) is the most efficient renal replacement therapy for a significant number of patients with ESRD. Kidney transplantation surgery is increasing in México; in the 1990 to 2002 period, an average of 895 KT were performed per year, at an annual 4% growth rate (1).

Survival of KT patients has increased because of improvements in candidates selection and study process, surgical techniques, immunosuppressive drugs and protocols, and a better surveillance and management of extra-renal risk factors (2), kidney allograft survival has thus reached, in the USA average values of 88.2% and 64.6% at one and five years for cadaveric donor transplants, and 93.8% and 76.3% at one and five years for living donor transplants (3), cardiovascular disease, and not ESRD, being now the most frequent cause of death in the KT patient (2,4).

Cyclosporin-A (CsA) is a drug used to prevent rejection of the kidney graft. It is a cyclic polypeptide calcineurin inhibitor. Its administration prevents the expression of genes for several cytokines whose activity is critical for lymphocyte T activation, including interleukins 2 and 4, gamma interferon, tumor necrosis factor α and others, thus preventing lymphocyte proliferation (2). The drug is used either alone or combined with other immunosuppressor drugs (2,4-5). Its use causes collateral effects, such as nephrotoxicity, hirsutism, arterial hypertension, dermatosis (2,6) and lymphoproliferative diseases (6).

Among the oral cavity collateral effects associated to CsA are gingival hyperplasia (GH) (6-8), opportunistic infections such as oral candidiasis (OC) and hairy leukoplakia (HL) (7,9), squamous cells carcinoma of the lips (9), and non-Hodgkin’s lymphoma (10-11).

Many reports have been published on the prevalence of gingival hiperplasia in kidney transplant patients. Reports on the prevalence of other oral mucosa lesions (OL) in these patients are, however, scarce. The aim of this study was to assess the prevalence of oral lesions in a group of kidney transplant patients from a social security institution, and analyze their possible association with one another, as well as with CsA use, nifedipine use, and relevant laboratory results and clinical variables.

PATIENTS AND METHODS

The study group comprised those patients attending the nephrology outpatient clinic for KT follow up in a Mexican Institute of Social Security (IMSS, for its initials in Spanish) hospital at San Luis Potosi, Mexico, during a 2-year period. Inclusion criteria were age older than 16 years and a functional kidney allograft. Patients undergoing dialysis because of definitive rejection of the kidney allograft were excluded. Verbal consent was asked for oral cavity examination. Information was obtained on cause of ESRD, date of KT, chronically used drugs, smoking, doses and whole blood CsA levels, total leukocyte count, serum urea and creatinine.

On clinical examination, oral mucosa lesions associated to solid organ transplant patients (9) were searched for: oral candidiasis, hairy leukoplakia, recurrent oral herpes, ulcerations, and gingival hiperplasia.

Lacking an Epstein-Barr virus (EBV) identification test or lesion biopsies, Hairy leukoplakia (HL) diagnosis was based on the presumptive HL clinical criteria from EC-Clearinghouse on oral problems related to HIV infection and the WHO Collaborating Center on oral manifestations of the immunodeficiency virus (12), describing HL as a grayish-white lesion on the lateral border of the tongue, which cannot be scraped off, may display vertical ridges, and does not respond to antimycotic treatment, or occurring in a state of demonstrated immunodeficiency. We called this a clinically compatible with hairy leukoplakia (CHL) lesion.

Oral candidiasis (OC) diagnosis was based on the clinical aspect of the lesion, and was confirmed by the demonstration of gemmating Candida sp hyphae on a PAS-stained exfoliative cytology, evaluated by two qualified in oral pathology specialists.

Herpes simplex (HS) was a clinical diagnosis, established when the patient presented erosions, ulcerations, or crust preceded by blistering on the vermilion borders or within oral mucosa.

Gingival hyperplasia, a frequently erythematous gum overgrowth with granular or lobulated aspect, was classified, according to Pernu’s modification (13) of the Angelopoulos and Goaz index, in three degrees: Grade O (G-0) normal gum, Grade 1 (G-1), a slight overgrowth and thickening of marginal gum, covering up to a third of the crown. Grade 1 (G-2), moderate gum overgrowth covering a half of the crown, and Grade 3 (G-3), severe gum overgrowth covering two thirds of the crown, or affecting all of adhered gum.

Oral hygiene (OH) was evaluated by examining six definite dental surfaces, according to a simplified oral hygiene index (S-OHI) (14): Hygiene was "Good" when 0-2 teeth presented bacterial plaque (BP) in up to one third of the clinical crown; "Fair" when 1-2 teeth presented BP or soft white residues in more than a third of the crown, or 3 to 4 teeth had BP in up to one third of the crown, and "Bad" when BP was present in more than two thirds of the surface of one of the examined teeth.

Descriptive statistics were obtained. GH was analyzed first by obtaining an average state of the gum, after dividend the teeth in sextants, and the highest GH degree sextant then classified the patient. A logistic regression model was used for GH association with other clinical variables, with GH the dependent variable, and age, S-OHI, CsA blood levels, and nifedipine use as independent variables. The possible association between other oral lesions, and between OL and renal function level estimated by serum creatinine, and total leukocyte counts, were analyzed with Pearson’s X² test or Fisher’s exact test, where appropriate. A P value <0.05 was considered significant.

RESULTS

Ninety patients were studied; 50 (55.5%) men and 40 (44.4%) women, with an mean age 31.4 ± 29.0 (range 16 to 63) years. Table 1 shows the causes of chronic renal failure. Median post KT time was 10 (range 1 to 187) months. Daily doses of immunosuppressor drugs were CsA 3.2±1.2 mg/kg, azathioprine 1.6±0.6 mg/kg, and prednisone 0.19±0.10 mg/kg. Sixty-six patients (74.4%) used one or more anti-hypertensive drugs: verapamil 53 (58.8%), enalapril 52 (55.5%), losartan 10 (11.1%), and nifedipine 9 (10%). Fourteen patients (15.5%) were using an anti-microbial drug at examination time.

Laboratory tests: CsA levels 214 ± 80 ng/ml, hemoglobin 13.6 ± 2.9 g/dl, total leukocyte count 4.8±2.7x10³/µl, urea 48±21 mg/dl, and creatinine 1.4±0.4 mg/dl. Seven patients (7.7%) reported smoking one or two cigarettes a week. The S-OHI score showed 42 (46.7%) patients to have "good", 37 (41.1%) "fair", and 11 (12.2%) had "bad" oral hygiene.

Sixty percent (54/90) of the patients had at least one pathological entity in the oral mucosa. Table 2 shows the identified OL and their prevalence. The most prevalent entity was a kind of saburral tongue (ST), found in 20 (22.2%) patients which occurred as a yellowish-white coat on the back of the tongue, which could not be scraped off with a blunt instrument, coexisting with slightly elongated (<3 mm) filiform papillae, and which was negative for Candida sp on a PAS-stained exfoliative cytology, showing instead large amounts of normal desquamated epithelial cells and non-identified bacterial colonies. This alteration was more prevalent in patients with less than one year after KT (P<0.05); no association was found between ST prevalence and CsA dose or blood levels, renal function, total leukocytes count, or oral hygiene.

Seventeen (18.7%) patients had oral candidiasis. Ten had the erythematous form on the back of the tongue, and two both on the tongue and on the hard palate. Three patients had simultaneous erythematous and pseudomembranous candidiasis. No association was found between OC and total leukocyte count, CsA dose or blood levels, prednisone or azathioprine doses, or antimicrobial use at examination time.

Compatible hairy leukoplakia prevalence was 12.2%; its presentation was statistically associated to OC: four patients had simultaneous OC and HL (P=0.0495, Fisher’s exact test), three of them with two clinical forms of OC. No association was found to other OL, CsA dose or blood levels, azathioprine or prednisone doses, antimicrobial agents use, total leukocyte count, or serum creatinine. Seven patients had herpes simplex infection, six on the vermilion borders and one on the hard palate’s mucosa. Three of them occurred as well in OC cases (P=0.059, Fisher’s exact test), one a patient two clinical forms of OC. No association was found to other variables.

Gingival hiperplasia was found in 44 (48.9%) cases. Table 2 shows total and by degrees GH prevalence. The most frequently affected sextants were the anterior teeth, 16 (17.8%) superior and 13 (14.4%) inferior, with an average G-2 (superior) and G-1 (inferior) GH. Logistic regression (Table 3), used to analyze possible GH association to age, oral hygiene, CsA blood level, and nifedipine use, was significant (P<0.001), oral hygiene being the largest contributing factor. Nifedipine use got a marginal figure (P=0.07). No association was found to CsA blood levels (P=0.29) or verapamil use.

In the present study, 60% of the KT patients had at least one OL. Saburral tongue is a scarcely mentioned entity in the kidney transplant patient literature. Tyldesley et al in 1977 (15) described white superficial plaques on the back of the tongue, resembling pseudomembranous candidiasis, in KT patients. Culture and cytological smear of the lesions however, did not identify Candid sp, but only epithelial cells and bacteria (coagulase-negative Staphylococci, Streptococcus, Lactobacillus, Neisserias, and coliforms). Also in renal patients, Hong-Seop et al. (16) reported thickening of the superficial layer of the tongue in 12.2% of a group of Korean ESRD patients on hemodialysis therapy. On a different context, an epidemiological study in ambulatory dental patients (17) reported this finding in 23.2%, and associated it to both habits (smoking, drinking black tea) and bad oral hygiene, but also to study population age, gender, and ethnicity, pointing out that the definition used for "thickening of the superficial tongue layer" by different research groups is variable, which partly explains differences in reported prevalences. In the present study, ST cultures or biopsies were not performed, and the PAS-stained cytological smear did not show Candida sp, but only normal desquamated cells and a large amount of non-identified bacterial colonies. No association was found between ST and bad oral hygiene. Only seven patients reported smoking one or two cigarettes a week. Cytological, histological, bacteriological, comorbidity and life style studies are needed to understand ST detection in KT patients.

Oral candiasis is an opportunistic infection, associated to multiple local and systemic risk factors (18-21). Reported prevalences in different-cause immunosuppressed patients are different: 15.1% in insulin-dependent diabetics (22), 36.6% in poorly controled type-2 diabetics (23), 17.4% in oral or pharyngeal carcinoma patients on radiotherapy (24), 27% in head and neck cancer patients on radiotherapy (25), and 37.8% in HIV/AIDS infection with low CD₄ lymphocyte counts and high viral load (21), 38.2% on first-time positive VIH serology patients (26). We found 17 (18.9%) oral candidiasis cases in the present study. Other studies in KT patient have reported 10.1% (7), 3.7% (27), 15.5% (20), and 42.9% (28); this last value was considered associated to triple-drug immunosuppression based on CsA, azathioprine, and prednisone. As in most reports (7, 20-25), erythematous candidiasis was most prevalent form of candidiasis with 13.3%. Other studies reported 3.8% (7) and 15.5% (20). Candida sp infection pathogenesis is complex; different reported prevalences are partly explained by different host features and numerous risk factors, which in transplant patients include the use of immunosuppressor drugs (28).

The simultaneous finding of two clinical forms of OC has been interpreted as severe immunosuppression in HIV/AIDS patients (21,26). Three out of four patients with this finding had recently had an acute kidney allograft rejection crisis, and received high-dose methylprednisolone, which explains acute-on-chronic immunosuppression.

The potential relevance of HL finding in this group of patients is, on the one side, a known etiological association to EBV (29), its high prevalence and predictive value for AIDS state in HIV-immunosuppressed patients (26,30), and its known association to severe immunosuppression in this condition (21,30). On the other side, HL has also been identified in other conditions: kidney transplant patients (31-34), multiple myeloma (35), acute lymphocytic leukemia (36), exceptionally in immunocompetent patients with no known risk factors (37-38), topical or systemic corticosteroid treatment for vesicle-ulcerative oral mucosa disease or bronchial asthma (39-40), and its finding could have different implications in different conditions. A reliable HL diagnosis requires EBV identification in epithelial cells (29, 31-38) or the finding of compatible cytopathic changes on exfoliative cytology (41), which were not performed in our patients. As the clinical appeareance of the lesion was compatible with HL and because it persisted after antimycotic treatment, the observed lesion was classified as compatible with HL, or CHL. In this study, the observed 13% prevalence of CHL was similar to 11.3% HL reported in British KT patients (7). The EBV is the known etiological agent in a number of post-transplant lymphoproliferative disease (PTLD) cases (9-11), a complication associated to drug immunosuppression, which may even occasionally remit by decreasing it (9). HL has been reported prior to PTLD diagnosis associated to EBV infection, in a patient with a heart transplant (42). Other authors found HL in bone marrow transplant patients with severe drug-immunosuppression, and it disappeared once the condition was resolved (43), confirming an association to drug-induced immunosuppression (33). On the other side, in comparative studies of immunocompromised versus healthy subjects, EBV DNA was found in the oral mucosa, without evidence of HL, by polymerase chain reaction, in 72.5% of KT patients vs. 30% in healthy controls (44), and 65% in KT vs. 42.2% in HIV (+) and 16.6% in healthy controls (45). Even though KT patients carried EBV more often in oral mucosa in those studies, we found CLV cases in KT patients to be less prevalent than reported HL prevalence in HIV infected individuals (26).

GH is a collateral effect of CsA use. Its reported prevalence goes from 22% to 77% (8,13,46-49); in the present study it was 48.9%. Grade-2 GH was most prevalent, and the most affected sextants were the anterior teeth (superior and inferior), as reported by other authors (8,50), with no conclusive explanation for the predominance of these sextants, those most accessible for tooth-brushing. Mouth breathing and oral mucosa dehydration have been considered factors (50). The etiology of GH is multifactorial (6,47,51). A higher prevalence has been observed in young age (8,49,51-53), high CsA blood or saliva levels (52) and use of calcium-channel blocker anti-hypertensive drugs (49,53). This study, confirmed reports by others (8,13,46,51) in that GH was associated to bad oral hygiene, but we were not able to find an association to CsA dose or blood levels or CsA treatment duration (49), and it was only marginally associated to nifedipine use, probably because the number of patients using this drug was low. Improvement in GH has been reported by implementing an adequate tooth-brushing technique, topical povidone-iodine application, and periodontal treatment (54-55). Tacrolimus, an immunomodulator drug that has replaced CsA in some solid organ transplant programs, seems to be associated to a significantly lower GH risk (2).

In conclusion, kidney transplant patients frequently have oral lesions, an observation which could make the systematic examination of oral cavity into a valuable tool for KT patient follow-up, sometimes offering immediate information on drug immunosuppression level and other relevant conditions, such as the risk for non-compliance with drug treatment because of cosmetic considerations, as in the case of GH in young patients. As is the case in the others transplant patients (56), oral hygiene monitoring is needed in KT patients to reduce GH prevalence and severity and other oral complications.

BIBLIOGRAFÍA        [ Links ]

2. Danovitch GM. Danovitch GM. Handbook of kidney transplantation. Philadelphia; Lippincott Williams & Wilkins. 2005.         [ Links ]

3. U.S. Renal Data System, USRDS 2004 annual data report: Atlas of End-Stage Renal Disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Disease, Bethesda, MD, 2004. Available on line at: http://www.usrds.org/adr.htm        [ Links ]

4. Matas AJ, Human A, Gillngham KJ, Payne WD, Gruessner RW, Kandaswamy R, et al. Five preventables causes of kidney graft loss in the 1990s ; a single-center analysis. Kidney Int 2002;62:704-12.         [ Links ]

5. Vincenti F. Immunosuppression minimization: Current and future trends in transplant immunosuppression. J Am Soc Nephrol 2003;14:1940-8.        [ Links ]

6. Marshall RI, Bartold PM. Medication induced gingival overgrowth. Oral Dis 1998;4:130-51.         [ Links ]

7. King GN, Healy CM, Glover M T, Kwan JTC, Williams DM, Leigh IM, et al. Prevalence and risk factors associated with leukoplakia, hairy leukoplakia, erythematous candidiasis, and gingival hyperplasia in renal transplant recipients. Oral Surg Oral Med Oral Pathol 1994;78:718-26.         [ Links ]

8. Daley TD, Wysocki GP, Day C. Clinical and pharmacologic correlations in cyclosporine-induced gingival hyperplasia. Oral Surg Oral Med Oral Pathol 1986;62:417-21.         [ Links ]

9. Seymour RA, Thomason JM, Nolan A. Oral lesions in organ transplant patients. J Oral Pathol Med 1997;26:297-304.         [ Links ]

10. Kuo PC, Dafoe DC, Alfrey EJ, Sibley RK, Scanding JD. Postransplant lymphoproliferative disorders and Epstein-Barr virus prophylaxis. Transplantation 1995;59:135-55.         [ Links ]

11. Maxymiw WG, Wood RE, Lee L. Primary, multi-focal, non-Hodgkin´s lymphoma of the jaws presenting as periodontal disease in a renal transplant patient. Int J Oral Maxillofac Surg 1991;20:69-70.         [ Links ]

12. EC-Clearinghouse on oral problems related to HIV infection and WHO Collaborating Centre on Oral Manifestations of the immunodeficiency virus. Classification and diagnostic criteria for oral lesion in H IV infection. J Oral Pathol Med 1993;22:289-91.         [ Links ]

13. Pernu HE, Pernu LMH, Huttunen KRH, Nieminen PA, Knuuttila MLE. Gingival overgrowth among renal transplant recipients related to immunosuppressive medication and possible local background factors. J Periodontol 1992; 63:548-53.         [ Links ]

14. Genco RJ, Goldman HM, Cohen DW. Periodoncia. México: McGraw-Hill; 1993.         [ Links ]

15. Tyldesley WR, Rotter E, Sells RA. Bacterial thrush-like lesions of the mouth in renal transplant patients. Lancet 1977;1:485-6.         [ Links ]

16. Hong-Seop K, Sung-Woo L, Sung-Chang Ch,Young-Ku K. Oral manifestations and salivary flow rate, pH, and buffer capacity in patients with end-stage renal disease undergoing hemodialysis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1999;88:316-9.         [ Links ]

17. Avcu N, Kanli A. The prevalence of tongue lesions in 5150 Turkish dental outpatients. Oral Dis 2003;9:188-95.         [ Links ]

18. Oksala E. Factors predisposing to oral yeast infections. Acta Odontol Scand 1990;48:71-4.         [ Links ]

19. Nikoskelainen J. Oral infections related to radiation and therapy immunosuppressive. J Clin Periodontal 1990;17:504-7.         [ Links ]

20. Al-Mohaya MA, Darwazeh A, Al-Khudair W. Oral fungal colonization and oral candidiasis in renal transplant patients. The relationship to Miswak use. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2002;93:455-60.         [ Links ]

21. Campo J, Del Romero J, Castilla J, García S, Rodríguez C, Bascones A. Oral candidiasis as a clinical marker related to viral load, CD4 lymphocyte count and CD4 lymphocyte percentage in HIV-infected patients. J Oral Pathol Med 2002;31:5-10.         [ Links ]

22. Guggenheimer J, Moore PA, Rossie K, Myers D, Mongelluzzo, Block HM et al. Insulin-dependent diabetes mellitus and oral soft tissue pathologies. II Prevalence and characteristics of Candida and candidal lesions. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2000;89;570-6.         [ Links ]

23. Molina D, Monroy RE, Arenas R, Fernández RF, Rubalcaba PJ, Fabian SMG. Frecuencia de candidiasis oral en pacientes diabéticos tipo 2 ambulatorios en el Hospital General Manuel Gea González. Estudio clínico micológico. Dermatología Rev Mex 2002:46:3-9.         [ Links ]

24. Ramirez-A V, Silverman S, Mayer P, Tyler M, Quivey J. Candidal colonization and oral candidiasis in patients undergoing oral and pharyngeal radiation therapy. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997;84:149-53.         [ Links ]

25. Redding SW, Zellars RC, Kirkpatrick WR, McAtee RK, Caceres MA, Fotherrgill AW, et al. Epidemiology of oropharyngeal Candida colonization and infection in patients receiving radiation for head and neck cancer. J Clin Microbiol. 1999;37:3896-900.         [ Links ]

26. Ramírez-AV, Esquivel PL, Irigoyen CE, Anaya SG, González RI. Asociación de lesiones bucales con el estado serológico para el VIH. Salud Publica Mex 2002;44:87-91.         [ Links ]

27. Greenberg MS, Cohen G. Oral infection in immunosuppressed renal transplant patients. Oral Surg 1977;43:879-85.         [ Links ]

28. Gupta KL, Ghosh AK, Kochhar R, Jha V, Chakrabarti A, SakhujaV. Esophageal candidiasis after renal transplantation: comparative study in patients on different immunosuppressive protocols. Am J Gastroenterol 1994;89:1062-5.         [ Links ]

29. De Souza YG, Greenspan D, Felton JR, Hartzog GA, Hammer M, Greenspan JS. Localization of Epstein-Barr virus DNA in the epithelial cells of oral hairy leukoplakia by in situ hybridization on tissue sections. N Engl J Med 1989;320:1559-60.         [ Links ]

30. Glick M, Muzka BC, Lurie D, Salkin LM. Oral manifestations associated with HIV-related disease as markers for immune suppression and AIDS. Oral Surg Oral Med Oral Pathol 1994;77:344-9.         [ Links ]

31. Syrjanen S, Laine P, Happonen R-P, Niemelä M. Oral hairy leukoplakia is not a specific sign of HIV infection but related to immunosuppression in general. J Oral Pathol Med 1989;18:28-31.         [ Links ]

32. Macleod RI, Long L Qi, Soames JV. Oral hairy leukoplakia in an HIV-negative renal transplant patient. Br Dent J 1990;169:208-9.         [ Links ]

33. Greenspan D, Greenspan JS, De Souza YG, Levy JA, Ungar AM. Oral hairy leukoplakia in a HIV-negative renal transplant recipient. J Oral Pathol Med 1989;18:32-4.         [ Links ]

34. Kanitakis J, Euvrard S, Lefrancois N, Hermier C, Thivolet J. Oral hairy leukoplakia in a HIV-negative renal graft recipient. Br J Dermatol 1991;124:483-6.         [ Links ]

35. Blomgren J, Bäck H. Oral hairy leukoplakia in a patient with multiple myeloma. Oral Surg Oral Med Oral Pathol Oral Endod 1996;82:408-10.         [ Links ]

36. Nicolatou O, Nikolatos G, Fisfis M, Belegrati M, Papadaki T, Oikonomaki E, et al. Oral hairy leukoplakia in a patient with acute lymphocytic leukemia. Oral Dis 1999;5:76-9.         [ Links ]

37. Eisenberg E, Krutchkoff D, Yamase H. Incidental oral hairy leukoplakia in immunocompetent persons. Oral Surg Oral Med Oral Pathol 1992;74:332-3.         [ Links ]

38. Felix DH, Watret K, Wray D, Southam J C. Hairy leukoplakia in a HIV-negative nonimmunosuppressed patient. Oral Surg Oral Med Oral Pathol 1992;74:563-6.         [ Links ]

39. Lozada-Nur F, Robinson J, Regezi JA. Oral hairy leukoplakia in nonimmunosuppressed patients. Report of four cases. Oral Surg Oral Med Oral Pathol 1994;78:599-602.         [ Links ]

40. Zakrzewska JM, Aly Z, Speight PM. Oral hairy leukoplakia in a HIV-negative asthmatic patient on systemic steroids. J Oral Pathol Med 1995;24:282-4.         [ Links ]

41. Dias EP, Rocha ML, Silva Junior A, Spyrides KS, Ferreira SM, Polignano GA et al. Oral hairy leukoplakia. Histopatologic and cytophatologic features of a subclinical phase. Am J Clin Pathol 2000;114:395-401.         [ Links ]

42. Casiglia J, Woo S-B. Oral hairy leukoplakia as an early indicator of Epstein-Barr virus-associated post-transplant lymphoproliferative disorder. J Oral Maxillofac Surg 2002;60:948-50.         [ Links ]

43. Epstein JB, Sherlock Ch, Wolber RA. Hairy leukoplakia after bone marrow transplantation. Oral Surg Oral Med Oral Pathol 1993;75:690-5.        [ Links ]

44. Ammatuna P, Capone F, Giambelluca D, Pizzo I, D´ Allia G, MargiottaV. Detection of Epstein-Barr virus (EBV) DNA and antigens in oral mucosa of renal transplant patients without clinical evidence of hairy leukoplakia (OHL). J Oral Pathol Med 1998;27:420-7.         [ Links ]

45. Ammatuna P, Campisi G, Giovannelli L, Giambelluca D, Alaimo C, Mancuso S, et al. Presence of Epstein-Barr virus, cytomegalovirus and human papillomavirus in normal oral mucosa of HIV- infected and renal transplant patients. Oral Dis 2001;7:34-40.         [ Links ]

46. Somacarrera ML. Hernández G, Acero J, Moskow BS. Factors related to the incidence and severity of cyclosporin-induced gingival overgrowth in transplant patients. A longitudinal study. J Periodontol 1994;65:671-5.         [ Links ]

47. Seymour RA, Jacobs DJ. Cyclosporin and the gingival tissues. J Clin Periodontol 1992;19:1-11         [ Links ] 48. Spratt H, Bommer S, Irwin CR, Marley JJ, James JA, Maxwell P, et a.l Cyclosporin associated gingival overgrowth in renal transplant recipients. Oral Dis 1999;5:27-31.         [ Links ]

49. King G, Fullinfaw R, Higgins TJ, Walker RG, Francis DMA, Wiesenfeld D. Gingival hyperplasia in renal allograft recipients receiving cyclosporin-A and calcium antagonists. J Clin Periodontol 1993;20:286-93.         [ Links ]

50. Thomason JM, Kelly P, Seymour RA. The distribution of gingival overgrowth in organ transplant patients. J Clin Periodontol 1996;23:367-71.        [ Links ]

51. Seymour RA, Ellis JS, Thomanson JM. Risk factors for drugs-induced gingival overgrowth. J Clin Periodontol 2000;27:217-23.         [ Links ]

52. Mc Gaw T, Lam S, Coates J. Cyclosporin-induced overgrowth: Correlation with dental plaque scores, gingivitis scores, and cyclosporin levels in serum and saliva. Oral Surg Oral Med Oral Pathol 1987;64:293-7.         [ Links ]

53. Hamid AK, Einollahi B, Ansari G, Bagher MM. The effect of cyclosporine with and without nifedipine on gingival overgrowth in renal transplant patients. J Can Dent Assoc 2003;69:236-41.         [ Links ]

54. De la Rosa GE, Bustamante RM, Mondragón PA. El efecto del control de la placa bacteriana en la hiperplasia gingival inducida por ciclosporina-A. Reporte de dos casos. Revista de Ciencias Clínicas 2002;3:81-5.         [ Links ]

55. Somacarrera ML, Lucas M, Scully C, Barrios C. Effectiveness of periodontal treatments on cyclosporine-induced gingival overgrowth in transplant patients. Br Dent J 1997;183:89-94.         [ Links ]

56. López LJ, Sabater RMM, Muñoz SJ, Rosello LLJ, Grañena BA. Evaluación y prevención de las complicaciones orales en los pacientes trasplantados de médula ósea. Estudio clínico. Med Oral 2000;5:345-54.        [ Links ]