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Skin disorders in renal transplant recipients: a retrospective study*

Background Immunosuppressive therapy, which is necessary to avoid graft rejection in renal transplant recipients, presents an increased risk of several pathologies, namely infectious and neoplastic. Objectives To identify the most frequent skin diseases and their clinical and demographical risk factors within a population of renal transplant recipients. Methods A retrospective study of renal transplant recipients referred to dermatology visit and observed for the first time from January 2008 to December 2014. Results The study included 197 patients, 120 men (60,9%). Mean age was 50,7 years (±13,4). 12 patients (6,1%) had previous skin cancer. Infections were the most frequent reason of referral (93/197; 44%). From the total referred, 18,3% (36/197) presented pre-cancerous lesions. Malignancy was diagnosed in 36 patients (18,3%), with 29 non-melanoma skin cancers (14,7%) and 7 Kaposi sarcomas (3,6%). Ratio of basal cell carcinoma to squamous cell carcinoma was 1,1:1. Non-melanoma skin cancer was significantly associated with older age (p = 0,002), male gender (p = 0,028), history of previous skin cancer (p = 0,002) and higher duration of immunosuppressive therapy (p<0,001). Study limitations Retrospective study, with data from the first visit in dermatology. We didn't made classification on skin-types. Conclusions The great incidence of cutaneous infections and skin cancer is responsible for a significant morbidity. It is important to assure the regular dermatological follow-up of renal transplant recipients, which will promote the prevention, an early diagnosis and an efficient treatment.


INTRODUCTION
In renal transplant, the use of immunosuppressive drugs, indispensable to avoid organ rejection, implies an increased risk of several infectious and neoplastic diseases. 1 Cutaneous infections have a very high incidence in patients submitted to renal transplant and are diagnosed in 55-97% of these individuals. 2 The incidence of cutaneous neoplasia, particularly of non-melanoma skin cancer, is well characterized, with an increased risk of 20-times in the case of basal cell carcinoma (BCC) and 65-times in the case of squamous cell carcinoma (SCC). 3,4 Cutaneous neoplasms appear at an earlier age and have a more aggressive behavior, with greater local invasiveness and a greater tendency to metastasize. 4,5 Knowledge on the spectrum of skin diseases that most frequently affects patients undergoing renal transplant, in particular the understanding of their clinical presentation and their severity, is fundamental to elaborate dermatological follow-up plans in order to enhance their quality of life and increase their longevity.
The objectives of this study were to characterize a series of patients undergoing kidney transplantation and to identify the most frequent skin diseases when referring to the dermatology clinic. We also aimed to identify sociodemographic and clinical risk factors for diagnosed cutaneous neoplasms.

METHODS
We performed a retrospective study, including 223 patients who underwent renal transplant after 1979, referred to the specialist consultation on Dermatology for Transplanted Patients between January 2008 and December 2014. In that period, a total of 1,070 dermatology consultations were performed for transplanted patients, 223 were first-time consultations and 847 were subsequent consultations.
The sample is of convenience and is not representative of the population of renal transplant patients in Portugal. All patients aged <16 years (n = 1) and those who underwent bone marrow transplantation (n = 2) or liver transplantation (n = 5) were excluded. Those who were maintained on hemodialysis after transplant rejection (n = 2) or who were waiting for transplantation (n = 16) at the time of the first visit were also excluded. From the initial con- Mann-Whitney test and chi-square test were used, with Cramer's V as a measure of association. Fisher's exact test was also used when any of the expected frequencies was less than five.
Patients' age at the time of the first consultation, after referral, ranged from 19 to 79 years, with a mean of 50.7 years and a median of 54 years (± 13.4 years).
In 25 patients, other dermatological conditions were diagnosed, not groupable in the previously specified categories (12.7%).

DISCUSSION
The present study allowed the characterization of the spec- In this study, therapy with regimens that included azathioprine was significantly associated with a higher incidence of viral infection. It is possible that this drug induces a more marked depletion in the number and function of Langerhans cells, a fact that justifies the relationship described and already verified in previous studies. 7,8 In renal transplant patients, infections tend to have a more severe course, with a more rapid and more intense progression, generating abnormally severe and sometimes atypical conditions. 1,9 Thus, knowledge on the spectrum of the various forms of clinical presentation plays a pivotal role for early diagnosis and appropriate therapy. It may also be necessary to use preventive therapies, namely drugs and vaccines used prophylactically. 6 In this study, non-melanoma skin cancer accounted for 14.7% of referrals to the dermatology clinic. This value is similar to that obtained by Fernandes, S. et al., who, in a sample of renal transplant recipients, recorded an incidence of 13.3% of this neoplasm. 6 In the present series, non-melanoma skin cancer was significantly associated with age, male gender, longer duration of immunosuppressive therapy, and with previous cutaneous neoplasia.
In general population, a ratio of 4:1 between BCC and SCC is reported. In the transplanted patients, with time, there seems to be an exponential growth in incidence of SCC and a linear growth of BCC, so that the inversion of the ratio described is observed. 10 In this study, no such inversion was observed, with the number of BCC being greater than that of SCC, reaching a ratio of 1.1:1. This fact is in agreement with the data present in other studies conducted in the Mediterranean region, in which there seems not to be the typical inversion of the Anglo-Saxon and Scandinavian countries, probably due to genetic differences and sun exposure habits. 11,12,13 Although there is an increased risk of melanoma in the population of renal transplant patients by 1.6 to 3.4 times in the European territory, 4 in this series, there was no diagnosis of any case of this neoplasia.
Pre-neoplastic lesions were also an important reason for consultation in this study (18.8%), especially actinic keratosis, responsible for 13.7% of the referrals. This value differs from others from studies conducted in the Portuguese population. On the one hand, it is superior to data from the study of Fernandes, S. et al., in which the incidence of this pathology was 5% in renal transplant patients 6 and it is, on the other hand, lower than those obtained by Borges-Costa, J. et al., whose value obtained was 24%. 12 In the present study, actinic keratosis was significantly associated with greater age, longer immunosuppression, azatoprine therapy and presence of history of cutaneous neoplasia. The risk of progression to malignant disease, which is proportional to the actinic damage, and the positive relationship between previous cutaneous neoplasia and the

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Garrido PM, Borges-Costa J  were observed, such as purpura (41%) and gingival hyperplasia (27%). 16 The lower reference rate observed in Portuguese studies, particularly in this series, may be the result of the effective treatment of these lesions by transplant teams, rather than a lower rate of occurrence. 6 The present study made it possible to emphasize the high prevalence of skin diseases in patients undergoing renal transplant.
These lesions have a strong impact on the quality of life of these patients, which may contribute to lower adherence to immunosuppressive therapy. 16 As such, it is important to recognize it and treat it properly and early, preferably in specialized centers.