CLINICAL SIGNIFICANCE OF GLUCOCORTICOID PHARMACODYNAMICS ASSESSED BY ANTILYMPHOCYTE ACTION IN KIDNEY TRANSPLANTATION

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Abstract
A number of studies have demonstrated the impact of glucocorticoid response of peripheral lymphocytes on kidney allograft survival, suggesting that the better the glucocorticoid selection, the better the clinical outcome. However, individual differences in pharmacodynamics of clinically important glucocorticoids have not been taken into account. Four glucocorticoids (hydrocortisone, prednisolone, methylprednisolone, and dexamethasone) were examined for their ability to suppress in vitro blastogenesis of mitogen-stimulated PBL obtained from 122 chronic renal failure (CRF) patients waiting for renal transplantation and 98 healthy volunteers. Concentrations of steroids that gave 50% inhibition of lymphocyte blastogenesis (IC50) were determined individually in order to compare steroids and subject groups. Graft outcomes in 36 kidney transplant recipients treated with prednisolone were compared retrospectively with the prednisolone pretransplant IC50 values. Lymphocyte response to each glucocorticoid showed wide deviations among the subjects. Prednisolone IC50 values of the CRF patients showed the largest deviation, ranging from 1.0 to 10,000 micrograms/L. Thus, a significantly large population of the CRF patients (26.2%), when compared with the healthy subjects (4.1%) showed a marked decrease in lymphocyte response to prednisolone (P < 0.01). The binding capacity and affinity of lymphocyte glucocorticoid receptors did not differ significantly between the responders and nonresponders, suggesting that steroid resistance is a post-receptor event. The antilymphocyte potency of prednisolone assessed by IC50 of the steroid was less than that of hydrocortisone, whereas methylprednisolone was > 12-fold superior to prednisolone. After kidney transplantation, CRF patients who showed impaired preoperative lymphocyte response to prednisolone had a significantly high incidence of acute allograft rejection under prednisolone/CsA therapy (P < 0.01). It is concluded from these results that methylprednisolone could be of benefit to prednisolone-resistant recipients, who can be identified by the preoperative lymphocyte culture.

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