Impaired Prednisolone Sensitivities of the Endocrine System and Peripheral-blood Lymphocytes are Closely Related to Clinical Incidence in Renal Transplantation

Abstract

Endocrine- and immune-responses to prednisolone and their relation to clinical incidence were assessed in 19 renal transplant recipients. All of the patients were treated with prednisolone and cyclosporin. Response of the hypothalamic-pituitary-adrenal (HPA) system to prednisolone was evaluated by measuring serum cortisol concentration. Cortisol concentration before transplantation was 126.7 +/- 38.6 ng mL-1, while it decreased to 4.1 +/- 2.5 ng mL-1 within the period characterized by a cumulative dose of prednisolone from 300 to 700 mg. A statistically significant high incidence (P less than 0.01) of acute rejections was observed in low HPA responders; (mean cortisol concentration during prednisolone treatment exceeded 3.0 ng mL-1), 6 of 12 with a low HPA response to prednisolone showed signs of rejection, while none of the 7 with a high HPA response showed signs of rejection. The concentrations of prednisolone suppressing the in-vitro response of pretransplant lymphocytes to concanavalin A by 50% (ID50) were determined. Lymphocytes from 8 patients were extremely insensitive (ID50 greater than 500 ng mL-1), and 5 of the 8 showed signs of rejection. Lymphocytes from the other 11 patients showed high sensitivity (ID50 less than 500 ng mL-1), and only one of those showed signs of rejection. Thus, a significantly high incidence of rejection was observed in low lymphocyte-responders to prednisolone (P less than 0.05). The results suggest that an insensitive endocrine response to prednisolone correlates with an impaired lymphocyte response to the steroid, and that both of the indices are related to occurrence of rejection. Evaluation of these pharmacodynamic parameters in combination may serve as a guideline for successful immunosuppressive therapy in renal transplantation.

Interindividual Glucocorticoid Sensitivity in Young Healthy Subjects: The Role of Glucocorticoid Receptor α and β Isoforms Ratio

“…Studies on the HPA axis sensitivity to GCs in young and elderly normal population have demonstrated that up to ten percent of normal subjects without DEX metabolism alterations can be considered glucocorticoid resistant, using no suppression of plasma and salivary cortisol after 1 mg DEX as end-point [18, 30 -32] . In an attempt to identify predictive factors of the response to GC, the pattern of DEX-mediated inhibition of Con-A stimulated PBMC proliferation has been used in different infl amma-tory and immune disease as asthma [34] , rheumatoid arthritis [35] idiopatic nephrotic syndrome [36] , and in patients awaiting renal transplantation [37] . These studies have demonstrated an increased incidence of lymphocyte resistance to the effects of GC in these disorders.…”

Cellular pharmacodynamics of immunosuppressive drugs for individualized medicine

“…Many reports have also demonstrated the relationship between PBMC-response to GCs in vitro and the clinical efficacy of GCs in renal transplant recipients [16,26,39,40]. According to the findings of these reports, recipients whose PBMCs were relatively resistant to the blastogenesis-suppressing effects of GCs showed a significantly higher risk of acute rejection episodes or graft loss during GC therapy [16,26,39,40]. Similarly, renal transplant recipients who exhibited poor PBMC-responses to cyclosporine have also been reported to show unsatisfactory clinical outcomes when treated with cyclosporine [17,41].…”

“…Based on the data for healthy subjects, the normal range upper-thresholds of PBMCresponse to immunosuppressants were established, and according to these ranges it might be possible to single out patient populations who are refractory to therapy with these drugs [16,17]. Many reports have also demonstrated the relationship between PBMC-response to GCs in vitro and the clinical efficacy of GCs in renal transplant recipients [16,26,39,40]. According to the findings of these reports, recipients whose PBMCs were relatively resistant to the blastogenesis-suppressing effects of GCs showed a significantly higher risk of acute rejection episodes or graft loss during GC therapy [16,26,39,40].…”

Immunosuppressant pharmacodynamics on lymphocytes from healthy subjects and patients with chronic renal failure, nephrosis, and psoriasis: Possible implications for individual therapeutic efficacy*

“…Ten milliliters of the heparinized blood was loaded on 3 ml of Ficoll-Hypaque solution, centrifuged at 13OOg for 15 minutes, and PBMCs, including lymphocytes, were separated as described previously. [14][15][16]20721 The cells were washed and resuspended in RPM1 1640 medium that contained 10% fetal calf serum, 100,000 III/L penicillin G, and 100 mg/L streptomycin, to a final density of 1 X lo6 cells/ml.…”

“…14-i7 In renal transplantation, recipients whose lymphocytes were resistant to glucocorticoids showed a high risk of acute allograft rejection or graft loss during glucocorticoid therapy. [8][9][10][11][12][13][14][15][16] Renal transplant recipients who exhibited poor lymphocyte response to cyclosporine have also been reported to show unsatisfactory clinical outcome when treated with cyclosporine. ",i8 It is therefore important to determine the distribution of the population of immunosuppressant "hyperresistant" patients, with the inclusion of glucocorticoids and cyclosporine, for several immunologic disorders and in organ transplant recipients.…”