Evidence for the Immunosuppressive Potential of Calcineurin Inhibitor-Sparing Regimens in Liver Transplant Recipients with Impaired Renal Function

Abstract

Patients requiring liver transplantation (LT) frequently experience renal insufficiency (RI), which affects their survival. Although calcineurin inhibitor-sparing immunosuppressive regimens (CSRs) are well known to prevent RI, the immune state in recipients receiving CSR remains to be intensively investigated. In the present study, we investigated the immune state in liver transplant patients suffering from RI received a CSR comprising a reduced dose of calcineurin inhibitor (CNI), methylprednisolone, and mycophenolate mofetil (MMF). For monitoring the immune-state response to anti-donor allostimulation in these patients, we employed a mixed lymphocyte reaction (MLR) assay using an intracellular carboxyfluorescein diacetate succinimidyl ester (CFSE)-labeling technique. Among 60 cases of living-donor LT at our institute, 68% of the patients had none to mild RI (non-RI group) and 32% of the patients had moderate to severe RI (RI group). The RI group received a CSR comprising reduced dose of tacrolimus, methylprednisolone, and MMF, while the non-RI group received a regimen comprising conventional dose of tacrolimus and methylprednisolone. One year after LT, the mean estimated glomerular filtration rate (eGFR) in the non-RI group had significantly deteriorated. In contrast, the mean eGFR in the RI group had significantly improved after LT, although it was still lower than that of the non-RI group. Notably, 53% of the patients in the RI group were completely cured of RI by 1 year after LT. None of the patients had severe RI at 1 year after LT nor required chronic hemodialysis during the observation period. Serial mixed lymphocyte reaction assays revealed that anti-donor T cell responses were adequately suppressed in both groups. To evaluate the immune status of these patients, we employed a serial MLR assay using a CFSE-labeling technique. In both groups, limited CD4+ and CD8+ T-cell proliferation was observed in the anti-donor responses as compared with the anti-third-party responses through the first year. At 1 month after LT, the average of stimulation index (SI) for CD4+ T cells in response to anti-third-party stimulation was >2 (the average value in healthy volunteers without any immunosuppressive treatment) i.e., there was a normal response in the anti-third-party. At 1 year after LT, the average of SIs for CD4+ and CD8+ T cells in response to both anti-donor and anti-third-party stimulation was < 2. There were no significant differences in acute rejection rates, bacterial, fungal, or cytomegalovirus infection rates and patient survival between the groups. In conclusion, patients with pre-transplant RI receiving CSR under immunological monitoring using an MLR assay were associated with less impairment of renal function without an increased frequency of rejection or patient survival. Anti-donor T cell responses were adequately suppressed in these patients as well as in patients who received the conventional immunosuppressive regimen comprising a standard dose of CNI.