Prevalence and clinical spectrum of skin diseases in kidney transplant recipients

Cutaneous lesions can be a significant problem in kidney transplant recipients. Factors such as climate and skin types have been implicated as modifiers of these clinical manifestations. With the purpose of determining the prevalence and clinical spectrum of skin diseases in a group of Hispanic kidney transplant recipients in a tropical climate, 82 serial unselected patients were examined. Seventy-eight were found to have some type of skin disease. Infections of the skin were the most common, followed by drug-induced changes and malignant or premalignant cutaneous tumors. Except for the preponderance of superficial mycotic infections, the overall results in our population are in agreement with other series.     

Metastasis of skin squamous cell carcinoma in kidney transplant recipients

Cutaneous squamous cell carcinoma (cSCC) is the most common skin malignancy in kidney transplant recipients (KTRs) as a result of immunosuppression. A worldwide increase in kidney transplantation justifies the determination of prognostic biomarkers by collecting detailed patient data on metastasis development. This study aims to characterize the clinical, epidemiological, and histopathological profiles of KTRs who developed metastasis of cSCC. We conducted a retrospective single-center study on 18 KTRs and 21 immunocompetent patients (ICs) with metastatic cSCC, using data from 2004 to 2021. ICs were older (median age 70.5 years) than KTRs (median age: 59.5 years). Both groups were predominantly male with Fitzpatrick skin phototype I/II. The primary tumor appeared around 83.5 months post-transplant, usually in sun-exposed areas (61.1%), though some non-exposed areas in ICs (23.8%) contradicted literature findings. KTRs took longer to develop metastasis (median: 11.0 months) compared to ICs (median: 5.5 months). The mean size of the primary tumor was smaller in KTRs (2.50 cm²) compared to ICs (4.55 cm²). The main lymph node chain affected by metastasis was parotid lymph nodes in KTRs (27.8%) and cervical/axillar lymph nodes in ICs (both 19.0%). Both groups exhibited similar primary tumor grades and metastasis evolution, but KTRs had a higher prevalence of lymphovascular invasion. Metastasis of cSCC was more common in males with low skin phototype, in KTRs, particularly on the head and neck. The study suggests a possible link between lymphovascular invasion and metastasis development in KTRs.     

Management of skin cancer in solid organ transplant recipients

The incidence of catastrophic skin cancer in the solid organ transplant population continues to rise. As transplant patients are living longer, it is likely that dermatologists will be looking after an increasing number of organ transplant recipients. The key to managing this patient population lies in a multidisciplinary approach encompassing patient education, skin screening in the immediate post-transplant period, regular follow-up, and rapid referral to a dermatologist once skin lesions suspicious for skin cancer are diagnosed. Of paramount importance is discussion with transplant physicians to negotiate reduction of immunosuppression in the setting of catastrophic skin cancer. This article defines the scope of the problem of skin cancer in the solid organ transplant population, defines the nature of the lesions commonly presented, and reinforces the benefit of a multidisciplinary approach in the management of these patients.     

Hypertension in kidney transplant recipients

Kidney transplantation is considered the treatment of choice for end-stage kidney disease patients. However, the residual cardiovascular risk remains significantly higher in kidney transplant recipients (KTRs) than in the general population. Hypertension is highly prevalent in KTRs and represents a major modifiable risk factor associated with adverse cardiovascular outcomes and reduced patient and graft survival. Proper definition of hypertension and recognition of special phenotypes and abnormal diurnal blood pressure (BP) patterns is crucial for adequate BP control. Misclassification by office BP is commonly encountered in these patients, and a high proportion of masked and uncontrolled hypertension, as well as of white-coat hypertension, has been revealed in these patients with the use of ambulatory BP monitoring. The pathophysiology of hypertension in KTRs is multifactorial, involving traditional risk factors, factors related to chronic kidney disease and factors related to the transplantation procedure. In the absence of evidence from large-scale randomized controlled trials in this population, BP targets for hypertension management in KTR have been extrapolated from chronic kidney disease populations. The most recent Kidney Disease Improving Global Outcomes 2021 guidelines recommend lowering BP to less than 130/80 mmHg using standardized BP office measurements. Dihydropyridine calcium channel blockers and angiotensin-converting enzyme inhibitors/angiotensin-II receptor blockers have been established as the preferred first-line agents, on the basis of emphasis placed on their favorable outcomes on graft survival. The aim of this review is to provide previous and recent evidence on prevalence, accurate diagnosis, pathophysiology and treatment of hypertension in KTRs.     

Sunlight, keratotic skin lesions and skin cancer in renal transplant recipients

In a retrospective follow-up study, 36 renal transplant recipients with, and 101 without, skin cancer, who had received their first transplant before January 1981 and who were still alive with a functioning graft on 1 August 1989, were assessed to determine the risk of non-melanoma skin cancer in relation to exposure to sunlight during childhood and adolescence. The contribution of the number of keratotic skin lesions to the skin cancer risk was also assessed. The estimated relative risks (odds ratios) of skin cancer in relation to exposure to sunlight and the presence of keratotic skin lesions were calculated by maximum likelihood estimation in a logistic model. The majority of skin cancers and keratotic skin lesions were confined to sun-exposed skin. After adjustment for possible confounding variables, the odds ratios of skin cancer for moderate and high cumulative life-time exposure to sunlight, respectively, compared with low exposure, were 2·4 (95% confidence interval [CI] 0·64-9·3) and 47·6 (95% CI 5·4-418). Exposure to sunlight before the age of 30 contributed more to the risk of developing skin cancer later in life than exposure after the age of 30. No association was found between cumulative life-time exposure to sunlight and the number of keratotic skin lesions. Nevertheless, these lesions behaved as a strong independent risk factor in the development of skin cancer. The adjusted odds ratio of skin cancer for 50-99 lesions compared with >50 lesions was 4·5 (95% CI 1·1-18·2); the adjusted odds ratio for ≥100 lesions compared with >50 lesions was 20·8 (95% CI 5·3-81·7). We conclude that exposure to sunlight before the age of 30 contributes more to the risk of skin cancer in renal transplant recipients than exposure after the age of 30. Cumulative life-time exposure to sunlight does not appear to be associated with an increased number of keratotic skin lesions in these patients. The preferential localization of such lesions on sun-exposed skin suggests a possible role of recently received exposure to sunlight in the development of these lesions.     

Sun habits in kidney transplant recipients with skin cancer: a case-control study of possible causative factors

Organ transplant recipients are frequently affected by skin cancer, which might also be a major cause of long-term mortality. Excessive sun exposure is considered to be a factor in the aetiology, but uncertainty about the importance of this and other proposed risk factors remains. The purpose of this study was to investigate sun behaviour before and/or after the transplantation in kidney transplant recipients with or without cutaneous squamous cell carcinoma. A nested, population-based, case-control study was carried out on 95 kidney transplant recipients who had contracted cutaneous squamous cell carcinoma after the transplantation and on an accurately matched control population of 154 kidney transplanted patients. Information on sun exposure before and after the transplantation, skin type, use of sunbeds, warts, etc., was obtained from a questionnaire which contained 38 detailed questions. The differences between cases and control subjects were not significant for sun exposure before or after the transplantation, sun protective measures, number of sunburns, outdoor occupation, smoking habits or use of sunbeds. Compared to patients with skin type IV, the cutaneous squamous cell carcinoma odds ratio was 3.0 (95% CI = 1.3-7.0) for skin type I + II. Patients with light blond or red hair colour also had a higher odds ratio than those with dark hair, 3.2 (95% CI = 1.2-8.2), and patients with warts after the transplantation had a higher odds ratio than those without, 2.2 (95% CI = 1.2-4.2). In conclusion, poor tanning ability rather than the amount of sun exposure is associated with the development of cutaneous squamous cell carcinoma in kidney transplant recipients and warts appearing after the transplantation indicate increased risk.     

Current approaches to skin cancer management in organ transplant recipients

Approximately 225,000 people are living with organ transplants in the United States. Organ transplant recipients have a greater risk of developing skin cancer, including basal cell carcinoma, squamous cell carcinoma, and malignant melanoma, with an approximately 250 times greater incidence of squamous cell carcinoma in certain transplant recipients, compared with the general population. Because skin cancers are the most common posttransplant malignancy, the resultant morbidity and mortality in these high-risk patients is quite significant.     

Human papillomavirus infection and skin cancer risk in organ transplant recipients

Warts and squamous cell carcinomas are important cutaneous complications in organ transplant recipients. The role of infection with human papillomaviruses (HPV) in the development of cutaneous squamous cell carcinoma is still unclear. An extremely diverse group of HPV types, mainly consisting of epidermodysplasia-verruciformis (EV)-associated HPV types, can be detected in benign, premalignant, and malignant skin lesions of organ transplant recipients. Frequently, there are multiple HPV types present in single skin biopsies. Typically, the prevalence of viral warts rises steadily after transplantation and a strong association exists between the number of HPV-induced warts and the development of skin cancer. The interval between the transplantation to the development of warts is clearly shorter than the interval from transplantation to the diagnosis of the first skin cancer. A comparison of transplant recipients with and without skin cancer, however, showed an equally high prevalence of EV-HPV DNA in keratotic skin lesions in both groups of patients and the detection rate and spectrum of HPV infection in hyperkeratotic papillomas, actinic keratoses, and squamous cell carcinomas was also similar. HPV DNA can frequently be detected in patients with hyperproliferative disorders like psoriasis and antibodies against HPV in patients with regenerating skin (e.g., after extensive second degree burns). Latent infection with EV-HPV seems to be widespread. The hair follicle region might be the reservoir of EV-HPV. The E6 protein from a range of cutaneous HPV types effectively inhibits apoptosis in response to UV-light induced damage. It is therefore conceivable that individuals who are infected by EV-HPV are at an increased risk of developing actinic keratoses and squamous cell carcinomas, possibly by chronically preventing UV-light induced apoptosis.     

Association of seborrhoeic warts with skin cancer in renal transplant recipients**

Background Renal transplant recipients (RTR) have a well recognized increased risk of cutaneous malignancy. A clinical observation that RTR with skin cancer often had multiple seborrhoeic warts prompted an investigation in RTR into the relationship between seborrhoeic warts and skin cancer and an exploration into potential risk factors for seborrhoeic warts in this population, including infection with human papillomavirus (HPV). Methods This was a case control study involving 308 RTR. Clinical examinations identified seborrhoeic warts. Histological records reviewed to look for evidence of prior cutaneous malignancy. Seroprevalence of antibodies to 34 different HPV types tested using multiplex serology. Odds ratios (OR) calculated using unconditional logistic regression analysis to look for associations between skin cancer, HPV infection and seborrhoeic warts, controlling for potential confounding factors of gender, age and time since transplantation. Results Seborrhoeic warts were associated with non‐melanoma skin cancer [OR = 3.7; 95% confidence intervals (CI) ranging from 1.6–8.9; P = 0.002] when confounding factors of gender, age and time since transplantation were controlled for. There was also an association between seborrhoeic warts and viral warts (OR = 3.0, CI: 1.6–5.4; P < 0.0001), but no association between seborrhoeic warts and infection with single or multiple HPV types. Conclusions Seborrhoeic warts are associated with cutaneous malignancy, but not with any of the HPV types tested. The reasons for this association are unclear. RTR with multiple seborrhoeic warts may require more regular cutaneous examination to monitor for early signs of skin cancer.     

Update on the pathogenesis of post-transplant skin cancer in renal transplant recipients

Remarkable advances in the field of transplantation over the last several decades have benefited many thousands of patients. Five-year survival ranges from 90% for a live donor renal transplant to 85% for a cadaveric renal transplant. However, with this success come the complications of chronic immunosuppression. Lifelong immunosuppressive treatment for adequate graft function results in reduction of immunosurveillance, with increased risk of various cancers leading to substantial morbidity and mortality in these patients. This review discusses multifactorial intrinsic and extrinsic factors contributing to the pathogenesis of skin cancers in renal transplant recipients and reviews potential solutions.     

Low-dose retinoid therapy for chemoprophylaxis of skin cancer in renal transplant recipients

Background Renal transplant recipients have an increased incidence of skin cancers, which may be multiple and aggressive. Objectives The purpose of this study was to examine the chemoprophylactic effects of low-dose etretinate (0.3 mg/kg/day) on skin cancer development in renal transplant recipients and to monitor retinoid toxic effects at this dose. Methods All skin lesions were counted and photographed prior to therapy with etretinate. Patients were assessed at monthly intervals for new skin lesions and for retinoid toxicity. Results Eleven renal transplant recipients participated. There was a significant reduction in the number of skin cancers which occurred during etretinate therapy compared with pre-treatment for 3 and 6 months of treatment, and a trend towards fewer skin cancers in the 12 and 18 month treatment periods. Side-effects were well-tolerated and no significant biochemical effects were observed. Conclusion Low dose etretinate is safe, well-tolerated and partially effective in chemoprophylaxis of skin cancer in renal transplant recipients.     

Metabolic bone diseases in kidney transplant recipients

Metabolic bone disease after kidney transplantation has a complex pathophysiology and heterogeneous histology. Pre-existing renal osteodystrophy may not resolve completely, but continue or evolve into a different osteodystrophy. Rapid bone loss immediately after transplant can persist, at a lower rate, for years to come. These greatly increase the risk of bone fracture and vertebral collapse. Each patient may have multiple risk factors of bone loss, such as steroids usage, hypogonadism, persistent hyperparathyroidism (HPT), poor allograft function, metabolic acidosis, hypophosphatemia, vitamin D deficiency, aging, immobility and chronic disease. Clinical management requires a comprehensive approach to address the underlying and ongoing disease processes. Successful prevention of bone loss has been shown with vitamin D, bisphosphonates, calcitonin as well as treatment of hypogonadism and HPT. Novel approach to restore the normal bone remodeling and improve the bone quality may be needed in order to effectively decrease bone fracture rate in kidney transplant recipients.     

HLA alleles in renal transplant recipients with nonmelanoma skin cancer in southeastern Brazil

Background: Renal transplant recipients are submitted to immunosuppression to avoid graft rejection, which makes them susceptible to various conditions. Furthermore, these individuals present malignant tumors more frequently than the general population, including nonmelanoma skin cancer. The individual genetic basis that acts in the pathogenesis of cutaneous cancer may present a protection or susceptibility factor for disease development. One of these factors is the HLA complex.Objective: To investigate HLA alleles association to the occurrence of nonmelanoma skin cancer in renal transplant recipients from Sao Paulo State.Methods: A total of 213 patients (93 renal transplant recipients with nonmelanoma skin cancer and 120 renal transplant recipients without nonmelanoma skin cancer) were evaluated by retrospective and cross-sectional study. Epidemiological, clinical and HLA typing data were found in databases. HLA class I (A, B) and class II (DR) alleles were compared to establish their association with nonmelanoma skin cancer.Results: Comparing renal transplant recipients with and without nonmelanoma skin cancer, the HLA-B*13 allele was associated with higher risk of developing nonmelanoma skin cancer while B*45 and B*50 alleles were associated with protection.Study limitations: The HLA A, B and DR alleles identification for the kidney transplantation routine is done by low and medium resolution techniques that do not allow discrimination of specific alleles.Conclusion: The involvement of HLA alleles in nonmelanoma skin cancer in renal transplant recipients was confirmed in this study. Renal transplant recipients with HLA-B*13 showed higher risk for developing a skin cancer (OR= 7.29) and should be monitored for a long period of time after transplantation.     

A population-based study of skin cancer incidence and prevalence in renal transplant recipients

BACKGROUND: Cancers occurring following solid organ transplantation are a rapidly growing public health concern. Defining the extent of the problem has been limited by surveillance systems with incomplete registration of cases and the paucity of reliable national incidence data. OBJECTIVES: To determine the incidence of all cancers following renal transplantation and to make a detailed examination of trends and patterns associated with postrenal transplant skin cancers. METHODS: Integration of data from the national renal transplant database and the national cancer registry in Ireland enabled accurate determination of the number of renal transplant recipients (RTRs) with skin cancers and other malignancies in the time period 1 January 1994 to 31 December 2001. RESULTS: We demonstrated a biphasic increase in skin cancer incidence following renal transplantation, determined by the age at transplantation. There was a steady increase in risk for older RTRs (age 50+ years) from year 2 post-transplant, whereas the increased risk in younger RTRs (age < 50 years) occurred later but much more significantly, reaching 200 times the risk for an age-matched nontransplanted population by year 6 post-transplant. The number of nonmelanoma skin cancers (NMSCs) registered in RTRs accounted for 1% of all NMSCs registered nationally over the study period. The standardized incidence rates for invasive NMSC (33-fold increase) and in situ carcinoma of the skin (65-fold increase) were significantly increased (P < 0.05). The risk for invasive squamous cell carcinoma (SCC) was increased 82-fold compared with the nontransplanted population. Male RTRs were at particular risk of invasive SCC at sun-exposed sites such as the scalp and the external ear. Risk of malignant melanoma and Kaposi sarcoma were also increased relative to the nontransplanted population. CONCLUSIONS: This comprehensive national study illustrates how rates of skin cancer in Irish RTRs have influenced the national incidence of skin cancer. The high incidence of SCC, basal cell carcinoma and Bowen's disease in the early post-transplant period for older patients and the cumulative risk in younger patients with increased duration of transplantation highlight the importance of implementing early and continued cancer surveillance regimens post-transplant.