Biomarkers as a Tool for Management of Immunosuppression in Transplant Patients

Abstract

Therapeutic drug monitoring is a well-established approach in transplantation medicine to guide immunosuppressive therapy. However, it cannot always predict the effects of immunosuppressive drugs on immune cells, because it does not reflect any aspect of an individual patient's immune system. Pharmacodynamic monitoring is a more recent strategy to provide information about the biologic effect of a specific drug or drug combination on the individual transplant patient. Currently, there is a large number of different biomarkers that either directly (specific markers) or indirectly (global markers) relate to the pharmacodynamic effects of immunosuppressive drugs and are under investigation as potential candidates to be introduced in clinical practice. Such biomarkers may be useful to identify patients at risk of developing acute rejection, infection, or cancer as well as patients who are suitable for minimization of immunosuppressant therapy and may be helpful to manage the timing and rate of immunosuppressant weaning. Serial longitudinal monitoring may allow maintenance of an individualized immunosuppressive regimen. Thus, biomarker monitoring is a potential complementary tool to therapeutic drug monitoring. This review summarizes the current state of knowledge about the use of a number of global or drug-specific pharmacodynamic biomarkers. It is not a comprehensive overview of the literature available, but rather an evidence-based reflection by experts who are intensively involved in scientific work in this field.

Biomarkers

“…The dose reduction was accompanied by an increase in gene expression and was free from adverse events such as acute rejections, so long as the residual expression remained below 30%. Therefore, a range between 20% and 30% has been proposed as optimal in long-term stable renal transplant recipients [2]. These results have in general been confirmed in single studies with pediatric and elderly kidney transplanted patients, as well in pilot studies with stable liver and heart recipients [30e33].…”

“…Examples of receptor proteins are CD25 (the interleukin-2 receptor) and CD71 (the transferrin receptor) [70]. Members of co-stimulatory molecules include CD26, CD28, CD30 and CD154 [2,70]. Examples of adhesion molecules on activated T cells include members of the integrin family, such as LFA-1 (lymphocyte function associated antigen 1) or VLA-4 (very late antigen 4) and ICAM-1 (intercellular adhesion molecule 1 or CD54), as well as CD2 (LFA-2), which belong to the immunoglobulin superfamily [71].…”

“…P70 S6 kinase phosphorylation is a marker of mTOR inhibition by sirolimus and everolimus [2]. Hartmann et al [11] reported, in a small study with 24 kidney transplant patients receiving sirolimus in combination with either calcineurin inhibitors (CNIs) or mycophenolate mofetil (MMF), on 70S6 kinase phosphorylation, which was assessed by Western Blot technique.…”

“…Therefore, the question arises as to whether TDM really sufficiently reflects pharmacodynamics. Measuring appropriate biomarkers in addition to immunosuppressive drug levels may be useful to predict the actual pharmacodynamic effect in an individual patient in order to achieve personalized immunosuppression [2].…”

Biomarkers in blood for individualization of the pharmacotherapy with immunosuppressive drugs after transplantation of solid organs

“…Pharmacokinetic monitoring can always only be a surrogate for the pharmacodynamic effect of therapy, and the therapeutic ranges are statistically determined target values on the basis of a large number of patients. Pharmacodynamic biomarkers, which specifically detect the effect of the drug on its pharmacological target molecule or, non-specifically, the general effect on the patient ' s immune system, therefore, are an attractive addition to TDM to achieve immunosuppression that is better adapted individually [2] . An assessment of the immunological status prior to the transplantation would be helpful in order to be able to adapt the therapy optimally immediately after the transplantation.…”