Description

Heart transplant is the only effective treatment for people with advanced heart failure. Major advances in allograft protection, such as improved combined immunosuppressive therapies, have led to progressive increases in post-transplant survival, but acute cellular and especially non-cellular rejection still represents a challenge for clinicians. Endomyocardial biopsy (EMB) is the current standard of care used to identify rejection after HTx, with at least 13 biopsies scheduled within the twelve months following transplantation.

The mortality rate, after this period, is approximately 3.5% per year and the causes of death range from primary graft failure and multiorgan failure, to neoplasms, renal failure and cardiac allograft vasculopathy. Although acute rejection can be well managed in most cases, episodes of cumulative rejection and chronic rejection are likely to contribute to long-term graft failure and graft vasculopathy. The current ISHLT (International Society for Heart and Lung Transplantation) classification system provides categories of severity of rejection, for both cellular and antibody-mediated rejection. It describes the degree of tissue damage and infiltration by inflammatory cells and states that the greater the infiltrate, the worse the rejection. The purpose of the evaluation is to guide doctors in treating rejection before symptoms appear. However, histological reading, like any diagnostic technique, is subject to false positives and false negatives.

The researchers propose to monitor TAC trough concentrations directly in EMBs, during the first year after transplantation (5 scheduled biopsies), from at least 25 de novo heart transplant recipients. The results will be analyzed and correlated with whole blood and with the minimum concentrations of PBMC (peripheral blood mononuclear cells) detected, for each patient, in the same 5 scheduled follow-up visits. Pharmacogenetic studies will focus on CYP3A4, CYP3A5 and ABCB1 gene variants. The ABCB1 gene encodes P-glycoprotein (Pg-p), an ATP-driven transmembrane transporter that acts as an efflux pump and transports TAC out of PBMCs and tissues. These researchers hypothesize that elevated cardiac expression of P-gp may reduce TAC uptake into cardiac (donor) tissue, may act as an important modulator of immunosuppressive effects, and thus have important therapeutic implications.

Main objectives

Tacrolimus is a critically dosed drug and therapeutic drug monitoring is mandatory to avoid under- and overexposure. However, rejection and drug-related toxicity occur despite pre-dose whole blood (blood [TAC]) tacrolimus concentrations being on target. Monitoring tacrolimus concentrations at the target site (within peripheral blood mononuclear cells ([TAC] cells)) and directly in endomyocardial biopsies ([TAC] EMB)) may better correlate with treatment efficacy.

The objectives of this study are:

1. study TAC trough concentrations in whole blood (blood [TAC]), PBMC (cells [TAC]), and EMB ([TAC]EMB) simultaneously, across 5 scheduled follow-up visits of 25 HTx recipients
2. identify genetic characteristics that influence the metabolism and distribution of tacrolimus in whole blood, cells and EMBs,
3. study the relationships between the three concentration profiles ([TAC]blood), [TAC]cells, [TAC]EMB) and clinical outcomes, during the first year after heart transplantation.