Barcelona Consensus on Biomarker-Based Immunosuppressive Drugs Management in Solid Organ Transplantation

Abstract

With current treatment regimens, a relatively high proportion of transplant recipients experience underimmunosuppression or overimmunosuppression. Recently, several promising biomarkers have been identified for determining patient alloreactivity, which help in assessing the risk of rejection and personal response to the drug; others correlate with graft dysfunction and clinical outcome, offering a realistic opportunity for personalized immunosuppression. This consensus document aims to help tailor immunosuppression to the needs of the individual patient. It examines current knowledge on biomarkers associated with patient risk stratification and immunosuppression requirements that have been generally accepted as promising. It is based on a comprehensive review of the literature and the expert opinion of the Biomarker Working Group of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology. The quality of evidence was systematically weighted, and the strength of recommendations was rated according to the GRADE system. Three types of biomarkers are discussed: (1) those associated with the risk of rejection (alloreactivity/tolerance), (2) those reflecting individual response to immunosuppressants, and (3) those associated with graft dysfunction. Analytical aspects of biomarker measurement and novel pharmacokinetic-pharmacodynamic models accessible to the transplant community are also addressed. Conventional pharmacokinetic biomarkers may be used in combination with those discussed in this article to achieve better outcomes and improve long-term graft survival. Our group of experts has made recommendations for the most appropriate analysis of a proposed panel of preliminary biomarkers, most of which are currently under clinical evaluation in ongoing multicentre clinical trials. A section of Next Steps was also included, in which the Expert Committee is committed to sharing this knowledge with the Transplant Community in the form of triennial updates.

Tolerance in liver transplantation: Biomarkers and clinical relevance

“…A consensus document that aims to help tailor IS has been developed by the Biomarker Working Group of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology[142]. …”

Therapeutic monitoring of immunosuppressive drugs in pediatric patients: special considerations

“…As solid organ transplants are also genome transplants, GefDNA could be determined in plasma and used as a marker of allograft injury [9]. This 'liquid biopsy' would be of special interest in the pediatric population as it bears the potential to redundantize organ biopsy for differential diagnosis of rejection, infection, or ischemia and thereby avoiding a potentially harmful procedure that needs general anesthesia.…”

“…The Barcelona Consensus on Biomarker-Based Immunosuppressive Drugs Management in Solid Organ Transplantation has accurately summarized the current knowledge on biomarkers associated with patient risk stratification and immunosuppressive requirements that have been generally accepted as promising [9].…”

“…Constant efforts to further individualize immunosuppressive therapy also comprise the identification of constitutive genetic markers that influence drug response [9]. This pharmacogenetic approach of monitoring has the potential advantage to allow monitoring even before treatment begins and is constant over an individual's lifetime [10].…”

Biomarkers in solid organ transplantation

“…An alternative approach is to assess the biological activity of the immunosuppressive drugs on the target enzyme . Direct determination of target enzyme activity would provide a straightforward pharmacodynamic approach to evaluating the effect of the immunosuppressant in the individual patient . As an example, for mycophenolic acid, the activity of inosine monophosphate dehydrogenase can be measured .…”