Short summary

Tacrolimus and mycophenolate are the standard of care in maintenance therapy in kidney transplanted patients. It is a clinically significant challenge to find the optimal dose for the patients. Too high doses cause kidney toxicity and viral infections. Too low doses increase the risk of organ rejection.

We propose that measuring tacrolimus inside the cells is the key to getting the dose right.

We will conduct a prospective multicentre clinical non-intervention study of 100 kidney transplanted patients. We will draw multiple blood samples from the patients on one occasion, and retrieve health data from their medical records.

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Rationale

Chronic kidney disease age-adjusted death rate has increased globally by 37 % from 1990 to 2013 making it one of the few diseases with growing mortality. The incidence and prevalence of kidney transplantations in Denmark is 250 per year, and 3,000 respectively. The 5-year graft survival is 90 %. We hope this study can contribute to increase this number.

Tacrolimus and mycophenolate are the cornerstones in the immunosuppressive therapy used to prevent organ rejection. Tacrolimus overexposure is associated with graft toxicity and increased risk of viral infections, while underexposure is associated with graft rejection. In clinical practice, blood tacrolimus concentration Therapeutic Drug Monitoring (TDM) is used to control the tacrolimus concentration. However, it has proven difficult to determine the optimal target-range because graft toxicity and rejection both still occur in patients within the target range. Tacrolimus is metabolized by CYP3A (liver enzyme), and transported by p-glycoprotein. Tacrolimus suppresses interleukin 2 and interferon γ pathways by inhibiting calcineurin phosphatase in the T lymphocytes. Lymphocytes are found as part of the peripheral blood mononuclear cells (PBMC). The first assay for measuring tacrolimus in PBMCs was published in 2009.

In contrast to tacrolimus, TDM of mycophenolate is not yet established. A prerequisite for studying mycophenolate in this regard is the development of a measure of exposure of the active compound mycophenolate acid and its glucuronide metabolite. This can be done by deriving a limited sampling strategy (LSS) from a frequently sampled patient cohort.

Goal: The goal of this project is to improve the lifespan of transplanted kidneys and decrease adverse effects of immunosuppressive therapy by increasing the dosing precision.

Objectives: We will conduct a prospective clinical study of 100 kidney transplanted patients. We will investigate the relationship between tacrolimus in the blood and in PBMC. We will use expression of NFAT (Nuclear Factor of Activated T Cells) regulated genes, donor specific antibodies, cytokine profiling, graft function, rejection reactions, and viral infections as endpoints. We will also develop limited sampling strategies for mycophenolate and tacrolimus.

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Description of the cohort

Our cohort consists of adult kidney transplanted patients followed in Odense, Esbjerg and/or Kolding. All patients are treated with the immunosuppressive drugs tacrolimus and mycophenolate, both twice daily.

Data and biological material

We will collect multiple blood samples from patients on one occasion at least three months after kidney transplantation.

We will collect retrospective baseline demographics, medication history, and clinical information from patient medical records, as well as information from the routine blood samples taken during outpatient clinic visits.

Collaborating researchers and departments

Department of Nephrology, Odense University Hospital

• Consultant, clinical lecturer PhD Helle C. Thiesson
• Consultant, clinical lecturer PhD Jan Carstens

Department of Clinical Pharmacology, Pharmacy and Environmental Medicine, University of Southern Denmark

• Professor, consultant MD Kim Brøsen
• Analytical chemist PhD Flemming Nielsen
• Postdoc PhD Erkka Järvinen

Department of Clinical Biochemistry and Pharmacology, University of Southern Denmark

• Consultant, clinical lecturer PhD Troels K Bergmann

Department of Clinical Immunology, Aarhus University Hospital

• Consultant, clinical lecturer PhD Pernille Koefoed-Nielsen

Nefrologisk Afsnit, Hospital of South West Jutland

• Senior registrator MD Heidi Dahl Christensen

Medicinske Sygdomme, Lillebaelt Hospital Kolding

• Specialist doctor in nephrology MD Rikke Juhl-Sandberg