Evaluation of Calcineurin Activity as a Biomarker of the State of Immunosuppression in Heart-Transplanted Patients

Background: Given the potential opportunities offered by a pharmacodynamic approach to finely tune the immunosuppressive (IS) strategies, we have conducted two clinical studies to monitor calcineurin activity (CN-a) for the first 24 months following heart transplantation (HTx). Methods: Patients were eligible if their IS treatment included cyclosporine (CsA). A pilot monocenter study was first conducted with 51 patients enrolled and CN-a measurement at least once a month during the first 6 months after HT and then every 3 months. Then, a tricenter study was conducted with 40 patients enrolled and CN-a measurements at a higher frequency than in the pilot study. CN-a was determined in mononuclear cells. Endomyocardial biopsies were routinely performed to assess acute rejection. Coronagraphy was yearly performed to assess chronic rejection/chronic allograft vasculopathy (CAV). The occurrence of infections and malignancies was recorded to assess adverse events related to over-immunosuppression. Results: In the pilot study, CN-a was linked to both acute rejection and CAV. The survival without acute rejection was significantly lower in patients who displayed CN-a values below 13 pmol/mg/min during the first 2 months after HTx as compared to patients who exhibited CN-a values above this level (9% vs 48%, p=0.002). The survival without CAV was significantly lower in patients who displayed CN-a values below 16 pmol/mg/min as compared to patients who exhibited CN-a values above this level (51% vs 84%, p=0.0135). In addition, the occurrence of cancer and infections tended to be higher in patients displaying very low CN-a levels. These preliminary results were confirmed in the tricenter study. Conclusion: These results show that both acute rejection, CAV and CsA-related adverse events were paradoxically accompanied by a decreased CN-a, similarly to our recent findings in lung transplantation (Sanquer et al, 2013). We anticipate that the low CN-a levels associated with rejection could contribute to the toxicity induced by CsA, especially as its dosage is generally increased when AR is suspected.