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Background: Long-term steroid immunosuppression has been associated with the prothrombotic state observed in renal transplant (RT) patients, in whom both hypercoagulability due to an increase of von Willebrand factor/factor VIII complex, and impaired fibrinolysis due to PAI-1 excess have been demonstrated. Our aim was to investigate the effect of steroid withdrawal on fibrinolytic capacity in a group of RT patients., Methods: The fibrinolytic study was performed in 28 RT patients under stable immunosuppression therapy with cyclosporine, azathioprine, and methylprednisolone; only 12 of these patients could repeat the study 6 months after steroid withdrawal. Euglobulin lysis time (ELT), tissue plasminogen activator activity (t-PA:act) and antigen (t-PA:Ag), PAI-1 activity (PAI-1:act), and antigen (PAI-1:Ag) were assayed on blood samples drawn before and 20 min after the venous occlusion test (VO)., Results: An hypofibrinolytic state due to a significant increase in PAI-1 levels was confirmed in RT patients receiving triple immunosuppression therapy. RT patient who stayed off steroids showed a significant shortening of ELT both before (P=0.01) and 20' after VO (P=0.005) at the 6-month control. Moreover, after steroid withdrawal, PAI-1:Ag levels decreased significantly (P=0.002) and normalized; in a similar manner PAI-1:act levels also showed a significant decrease both before (P=0.001), and after VO (P=0.0001). The prevalence of RT patients with impaired fibrinolytic capacity was as high as 83.3% during steroid treatment, and dropped to 16.7% after steroid withdrawal., Conclusions: Our findings confirm that steroid withdrawal may normalize impaired fibrinolytic capacity in RT patients; this improvement may further contribute to reduce the thrombotic risk associated with renal transplantation.

Thromboembolic complications constitute an important risk in renal transplant patients, in whom a hypercoagulable state is associated with immunosuppressive treatment, and the presence of hypercoagulability and hypofibrinolysis specifically with cyclosporine. Hypercorticism secondary to steroid treatment has been associated with a thrombophilic state and the presence of a reduced fibrinolytic potential in particular. The aims of this study were to first evaluate the fibrinolytic potential by the venous occlusion (VO) test in 19 renal transplant (RT) patients, and then compare these findings with those obtained in similar groups of normal subjects and patients with Cushing's disease. The following tests were carried out before and after the VO test: euglobulin lysis time and t-PA and PAI-1 activities and antigen. Compared with normal controls, RT and Cushing's patients both showed a similar significant increase in PAI-1 activity and concentration. The VO test revealed a similar impairment in fibrinolytic potential in both the RT and Cushing groups. High and pathological PAI-1 levels before and after the VO test were consistent with a defective fibrinolytic potential due to the inhibitory effect of PAI-1 on plasminogen activation. A hypofibrinolytic state was found in 68.4% of RT patients. Our results suggest that an imbalance in the fibrinolytic system is a typical feature of RT patients one year after transplantation. Steroids appear to be the immunosuppressive drug mainly involved in determining thromboembolic risk after renal transplantation.

Drug-mediated tumor antigens (DMTA), which appear after in vivo treatment of murine lymphomas with 5-(3,3'-dimethyl-1-triazeno)-imidazole-4-carboxamide (DTIC), are shown to elicit strong primary cell-mediated responses in vitro. Specific cytotoxic response is obtained using CD2F1 (H-2d/H-2d) spleen cells cocultured in vitro for 5 days with inactivated histocompatible L5178Y/DTIC lymphoma cells in a one-way mixed lymphocyte tumor culture. Sensitized lymphoid cells are markedly cytotoxic for L5178Y/DTIC targets and are minimally or not active against the parental lymphoma. Marginal or no cross-reactivity is found between L5178Y/DTIC lymphoma and other untreated or DTIC-treated tumor or normal cells. Cytotoxic activity is T dependent, since it is abrogated by treatment in vitro with anti-serum and complement and is not elicited by spleen cells of athymic (nude) donors.

The immunodepressive and bone marrow stem cell-reducing activities of imidazole-4-carboxamide,5-(3,3-dimethyl-1-triazeno) (DTIC), an antitumoral agent reported to possess little immunodepressive capacity in man, have been investigated in mice and compared with those displayed by cyclophosphamide (Cy). In this species, single doses of DTIC could profoundly depress antilymphoma allograft resistance as well as the number of antibody-producing cells after primary and secondary stimulation with sheep erythrocytes. The highest immunodepressive activity was observed when DTIC was given before antigen and the effect observed was substantially more long lasting than seen with Cy, which was, however significantly more active on a milligram per kilogram basis. In contrast, both agents displayed a quantitatively equal activity in reducing bone marrow stem cells. It is concluded that DTIC can be an effective immunodepressant and that this activity may have clinical implications.