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Tacrolimus, the cornerstone of most immunosuppressive regimens in solid organ transplantation, is characterized by a narrow therapeutic window and high pharmacokinetic- and pharmacodynamic variability. Important sources of pharmacokinetic variability include the activity of intestinal and hepatic enzymes and transporters (namely cytochrome P450 enzymes CYP3A4, CYP3A5 as well as P-glycoprotein (P-gp)). Therapeutic drug monitoring is part of routine clinical practice but cannot resolve several key issues, such as predicting the magnitude of drug interactions, longitudinal variation in tacrolimus disposition and individual susceptibility to tacrolimus toxicity, particularly its nephrotoxity.This project aims to develop a comprehensive pharmacologic model for tacrolimus in renal recipients that includes genetic polymorphisms relevant to drug metabolism, clinical parameters and functional assessment of in vivo CYP3A4 and P-gp activity using validated drug probes. Additionally, the impact of kidney genotype on renal metabolism of tacrolimus (including metabolite generation) and the resulting nephrotoxicity will be assessed in vitro and in vivo. The in vitro model is based on conditionally immortalized human proximal tubular epithelial cells (ciPTEC) with varying CYP3A5 and P-gp genotypes. In vivo assessment will be performed by prospectively evaluating the effects of genetic polymorphisms on production of tacrolimus metabolites in stable renal recipients, and correlating this with the occurrence of tacrolimus nephrotoxicity (assessed on renal allograft protocol biopsies).

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Background: The COVID-19 pandemic has a great impact on solid organ transplant (SOT) recipients due to their comorbidities and their maintenance immunosuppression. So far, studies about the different aspects of the impact of the pandemic on SOT recipients are limited. Objectives: This systematic review summarizes the risk factors that make SOT patients more vulnerable for severe COVID-19 disease or mortality and the impact of immunosuppressive therapy. Furthermore, their clinical outcomes, mortality risk, therapeutic options and COVID-19 vaccination efficacy are discussed. Methods: A systematic search on PubMed was performed to select original articles on SOT recipients concerning the following four topics: (1) mortality and clinical course; (2) risk factors for mortality and composite outcomes; (3) maintenance immunosuppression and therapy; (4) vaccine immunogenicity. Relevant data were extracted, analyzed and summarized in tables. Results: This systematic review includes 65 articles. Mortality was associated with advanced age. Post-transplantation time or comorbidities were variably identified as independent risk factors for mortality or severe disease. However, generally, no comorbidity was reported as a major risk factor. SOT recipients have a higher risk of acute kidney injury, but no higher rate of mortality compared to non-transplanted patients was found. Immunosuppression and therapy were individually adjusted, without leading to high rates of graft dysfunction. Generally, no association between type of immunosuppression or treatment and mortality was found. At last, SOT patients experience a diminished immune response after two-dose vaccination with SARS-COV-2-mRNA-vaccines. Conclusion: More research is needed to address the direct effect of COVID-19 disease on the graft in lung transplant recipients, as well as the factors ameliorating the immune response in SOT recipients.

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Invasive fungal infections constitute an important cause of morbidity and mortality in solid organ transplantation recipients. Since solid organ transplantation is an effective therapy for many patients with end-stage organ failure, prevention and treatment of fungal infections are of vital importance. Diagnosis and management of these infections, however, remain difficult due to the mixed clinical presentation in addition to the lack of accurate diagnostic methods. The implementation of fungal biomarkers could lead to a more accurate and faster diagnosis, resulting in improved clinical outcomes. These novel diagnostic markers are nonetheless not routinely used. As the evidence for optimal prophylactic approaches remains inconclusive, considerable variation in the administration of prophylaxis persists. Current guidelines regarding fungal infections are not specifically aimed for solid organ transplantation recipients and recommendations for antifungal susceptibility testing are impacted by previous treatment regimens, which can alter the distribution of different pathogens. Furthermore, the increasing use of antifungals also contributes to incremental costs and the risk of development of drug resistance. This review will highlight risk factors, clinical manifestations and timing of fungal infections and will focus predominately on the current evidence for diagnosis and management of fungal infections.

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Chronic immunosuppressive therapy poses the organ transplant patient at increased risk for development of cutaneous malignancies. Skin cancer in this population exhibits distinct epidemiological, pathophysiological, behavioral, and prognostic features from the general population and should be managed differently. Organ transplantation is common in modern medicine and because of improved post-transplant care, more post-transplant courses are being complicated with skin malignancy. Over the last few years much data has emerged on the prevention and management of skin malignancy in transplant patients, but no recent compilation of this evidence with focus on therapy of non-melanocytic skin cancer is available. This review focuses on the features and management of post-transplant squamous cell carcinoma, basal cell carcinoma, Kaposi sarcoma, and Merkel cell carcinoma. The mainstay of management is surgery. Revision of immunosuppression gains more importance in aggressive variants of the cancer. Recent evidence on targeted therapy such as Hedgehog-inhibitors, endothelial growth factor receptor inhibitors, and checkpoint inhibitors is available but their roles are yet to be elucidated. This review makes recommendations and should serve as a guide for the dermatologist, the surgeon, or general practitioner encountering a post-transplant-patient with non-melanocytic skin cancer