Key words : Immunosuppression, Renal transplantation, Skin infections

Introduction
In Tunisia, the number of kidney transplant recipients is on the rise every year as a result of surgical and medical advancements. Kidney transplant provides a better standard of care for the increasing number of patients with end-stage renal disease, reducing long-term morbidity and mortality. However, the use of immunosuppressive drugs among transplant recipients, indispensable to avoid organ rejection, implies an increased risk of several infectious and neoplastic diseases.¹ Skin conditions range widely from skin cancers and skin infections to drug-induced skin disorders such as acne and sebaceous gland hyperplasia.^2,3 Studies on skin manifestations in kidney transplant patients have been predominantly from the West, and there is paucity of data on skin lesions in kidney transplant recipients from North African countries.

Knowledge on the spectrum of skin diseases that most frequently affect patients undergoing kidney transplant, in particular the understanding of their clinical presentation and their severity, is fundamental to elaborate dermatological follow-up plans in order to enhance quality of life and increase longevity of transplant recipients.^4,5

The objectives of this study were to characterize patients undergoing kidney transplant and to identify the most frequent skin diseases. We also aimed to identify sociodemographic and clinical risk factors for diagnosed lesions.

Materials and Methods
We reviewed the medical records of 200 kidney transplant recipients at Sahloul Teaching Hospital, Tunisia, between November 2007 and January 2018. Among these patients, we obtained clinical data of patients who sought skin consultations with either dermatologists or plastic surgeons within the hospital. We collected patient sociodemographic data, type of donor, and type of immunosuppressive therapy. We also obtained history of skin lesions and examination findings. After diagnosis, skin lesions were classified as follows: drug-related manifestations, skin infections, and skin neoplasms. All neoplasm diagnoses had histological confirmation. Duration of immunosuppressive therapy was estimated from the date of transplant to the date of the specialty visit.

We performed statistical analysis using SPSS software version 20 (SPSS Inc), with significance level of 5%. We used nonparametric Mann-Whitney test and the chi-square test, with Cramer V as a measure of association. We used the Fisher exact test when any of the expected frequencies was less than 5.

Results
We included 200 patients in our study cohort. The general characteristics of these patients are summarized in Table 1. Among these patients, 131 (65.5%) were male and 69 (34.5%) were female. Age ranged from6to75 years, with a mean age of 30.51 ± 12.0 years.

Patients had received kidneys from either living or deceased donors, with available data indicating 193 (96.5%) living donors and 7 (3.5%) deceased donors. Among transplant recipients, 97 patients (48.5%) had skin lesions. The mean time interval from transplant to first skin consultation was 31.3 months (range, 3 months to 10 years).

Table 2 shows the various skin conditions that were diagnosed. There were 61 cases (62.9%) of skin infections: 58 (59.8%) were drug-induced skin conditions and 3 were skin cancers; 73 were (37.8%) other skin conditions. Skin infection was the predominant reason for consultation, with viral warts (32.0%, n = 31) being the most common infection.

Cutaneous infections were noted in 61 patients (62.9%), with viral infection in 31 cases (50.8%), fungal lesions in 29 cases (47.5%), and bacterial in 7 cases (11.5%); viral and fungal skin lesions coexisted in 6 patients.

These were intercostal zona lesions in 5 cases (Figure 1), varicella in 6 cases, and herpetic lesions in 7 cases (Figure 2). Warts were noted in 13 cases, including 3 cases of anogenital condyloma (Figure 3).

Skin lesions secondary to immunosuppressants and corticosteroids were reported in 58 cases (59.8%), with mean time to onset of 53.5 ± 27.8 months (range, 3-120 months). Acne was the most frequently found condition (n = 35) (Figure 4).

Three patients (2.9%) developed Kaposi sarcoma (2 men, 1 woman), who were 33, 35, and 49 years old. All patients had received induction treatment with polyclonal antibodies (antithymocyte globulin) in combination with methylprednisolone. For maintenance treatment, the 3 patients received corticosteroid, mycophenolate mofetil, and tacrolimus combination. Tumor appeared, respectively 5, 15, and 43 months after transplant. Lesions were located in the amygdala in 1 patient, the palate in 1 patient, and the right foot in 1 patient. Treatment was a switch to mechanistic target of rapamycin inhibitor (sirolimus) in the 3 patients, with 2 patients requiring surgical resection. Remission was observed in all 3 patients. Renal graft loss was noted in 1 patient without recurrence.

Male sex was associated with a significant risk of skin complications after kidney transplant(P = .046). The extrarenal epuration method and duration did not increase the risk of skin lesions posttransplant (P = .12 and P = .13, respectively). We found no correlation between the occurrence of skin lesions and the type of donor (P = .9). Regarding immunosuppressive treatment, only maintenance cyclosporin treatment was significantly associated with occurrence of skin lesions after kidney transplant (P = .03). Of note, cutaneous involvement posttransplant was significantly associated with a longer duration of immunosuppression (P = .031) (Table 3). Multivariate analysis showed that the independent risk factors for the occurrence of skin lesions after kidney transplant were long duration of immunosuppression (P = .01) and cyclosporin as maintenance treatment (P = .02).

Discussion
Kidney transplant recipients have an increased risk of developing variable posttransplant skin manifestations. Among possible skin manifestations are skin infections, skin cancers, and lesions secondary to immunosuppressive treatment.⁶ Damage from these manifestations can lead to an alteration in quality of life of transplant recipients and additional morbidity, especially with presence of neoplasia.^7,8 We had a study sample size larger than some previous studies.^6,9,10

Among our study patients, prevalence of skin lesions was 48.5%. This result was comparable to data from several series in the literature,^4,9 with Bakr and colleagues, Savoia and colleagues, and Garrido and colleagues noting prevalences of 92%, 76%, and 83% respectively.^11-13

In a study from 2017 of 197 patients, 44% had skin infections.¹² Similarly, Prakash and colleagues reported that skin lesions of infectious origin are the most frequent (68%) followed by drug-induced skin lesions (44.4%).¹⁴ Among our study patients, the most common etiology of skin manifestations after kidney transplant was infection (62.9%), which was consistent with some previous studies (48.9%-84%).^15-18 There was a predominance of viral infections followed by fungal infections and then bacterial infections, a finding comparable to that from Garrido and colleagues.¹³ However, fungal infections were the most common in other publications.^14,19,20

Most patients with skin manifestations in our study were male (65.5%), which is comparable to several previous studies.^9-11,21 Male sex was significantly correlated with occurrence of skin lesions after kidney transplant in our study and that of Euvrard and colleagues.²⁰

Patients who received maintenance cyclosporin were more at risk of developing dermatological complications, which is similar to data in the literature. Indeed, among 486 kidney transplant recipients, treatment with cyclosporin and azathioprine was significantly associated with the development of infectious and cancerous skin lesions.²⁰ Taking cyclosporin was also associated with the development of warts in several studies.^1,21-23

In our series and in previous studies, skin manifestations after kidney transplant were significantly associated with longer duration of immunosuppression.^24-28 Ramsay and colleagues described prevalence of skin lesions of 44.3% after 5 years of transplant, with 52.3% after between 5 and 10 years and 56.9% after 10 years of immunosuppression.24 Pruvost and colleagues described a prevalence of warts of 16% after the first year of kidney transplantation, with prevalence of 35%, 45%, and 54%, respectively, 3, 5, and 7 years after kidney transplant.²⁹

Conclusions
Despite the retrospective nature of the study, with limited statistical analysis of the results and their comparisons to the data in the literature, our study corroborated with previous results by underlining the high prevalence of dermatological complications after kidney transplant. Therefore, appropriate follow-up of kidney transplant recipients is crucial, with periodic evaluations from pretransplant, as well as close collaboration between the dermatologist and nephrologist for optimal care.

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