Higher Sensitivity of Peripheral Blood Lymphocytes to Endogenous Glucocorticoid in Renal Transplant Recipients Treated with Tacrolimus, as Compared to Those Treated with Cyclosporine

Abstract

Background: Steroids in maintenance immunosuppressive drugs produce severe adverse events, and therefore, the use of steroids is withdrawn for many renal transplant recipients. However, steroids need to be restarted to prevent the worsening of renal function because of rejection episodes in some patients or in patients who experience steroid withdrawal syndrome. Currently, there are no indicators to predict which patients can sustain steroid withdrawal. Lymphocyte sensitivity to endogenous glucocorticoid cortisol could be a biological marker for safety reduction and steroid withdrawal. We examined relationship between lymphocyte sensitivity to cortisol in vitro and clinical outcome after steroid reduction or withdrawal in the renal transplant recipients. We also compared peripheral lymphocyte sensitivity to cortisol between transplant recipients treated with tacrolimus (Tac) and those treated with cyclosporine. Methods: The suppressive efficacies of cortisol against T-cell mitogen stimulated proliferation of peripheral lymphocytes was investigated in totally 41 patients with renal tramsplant patients, who were reducedor withdrawnsteroid. Nineteen out of the 41 patients were treated with Tac and the other 22 patients with cyclosporine A (CyA). Relationship between lymphocyte sensitivity to cortisol invitro and clinical outcome after steroid reduction or withdrawal was evaluated in 30 out of 41 renal transplant recipients. The lymphocyte sensitivity to cortisol was compared between 19 patients treated with Tac and 22 patients treated with CyA. Results: The cortisol IC50 values in the Tac and CyA groups were 0.09 ± 0.12 and 14.2 ± 12.7ng/ml, respectively. Lymphocyte sensitivity to cortisol in the Tac-treated group was significantly higher than that in the CyA treated group (p =0.0283). On the other hand, incidences of steroid withdrawal syndrome and increase in serum creatinine concentration were not significantly different between the Tac and CyA groups. Lymphocyte sensitivity to cortisol and its relationship with the clinical outcome after steroid reduction and withdrawal was investigated in 30 long stable renal transplant recipients. Serum creatinine levels increased in a significantly higher number of patients with lymphocytes hyposensitive to cortisol (IC50 ≥ 10000 ng/mL) than in normally sensitive patients (IC50 < 10000 ng/mL) (P < 0.005). The incidences of steroid withdrawal syndrome (P< 0.05) and necessity for increasing steroid dose or restarting steroid administration (P< 0.005) were also higher in the patients hyposensitive to cortisol than in normally sensitive patients. The patients in whom the lymphocyte proliferation rate was less than 60% did not show increase in S-Cr levels, experience steroid withdrawal symptoms, or require an increase in the steroid dose or restart of steroid administration. Conclusion: We considered from these observations that the lymphocyte sensitivity to cortisol would be useful for selecting patients for whom steroids should be withdrawn, and as a biomarker to safely reduce and withdraw steroids. Lymphocyte sensitivity to cortisol was higher in the Tac treated patients than that in the CyA treated ones. Since the cortisol sensitivity of peripheral lymphocytes is suggested to be a predictive marker for safe steroid withdrawal as described above, Tac administration shows promise in aiding successful withdrawal of steroid in long-term renal transplant recipients.