This chapter reviews tacrolimus and other immunosuppressive macrolides in clinical practice. Tacrolimus and rapamycin are classified as immunosuppressant drugs that are essentially macrolide derivatives. Tacrolimus inhibits T-cell activation at an early stage of the cell cycle through a calcium-mediated signal. It impedes the early phases of the immune signal transduction pathway in the cell by inactivating the dephosphatase activity of calcineurin. Tacrolimus is regarded as a significant agent in the treatment of a large number of immunologically mediated diseases. The role of tacrolimus-based primary immunosuppression in the prevention of rejection following solid organ transplants, especially liver and kidney transplants is well established. Its unique properties have led to its ability to rescue patients who have experienced rejection while on conventional cyclosporin-based immunosuppressive regimens. On the other hand, rapamycin (sirolimus) is another macrolide antibiotic that possesses potent immunosuppressant activity. Its chemical structure is partially similar to that of tacrolimus. The immunosuppressive effects of rapamycin result from its inhibition of T-cell and B-cell proliferation. The key effect on those cells results from the blocking of the signals of several cytokines, thus leading to interruption of the cell cycle from the G1 to the S phase. Rapamycin is investigated as an adjunctive immunosuppressant agent for prevention of rejection after organ transplantation in combination with cyclosporin and tacrolimus.

THE EFFICACY of tacrolimus in primary renal transplantation! led us to evaluate this agent for rescue of resistant allograft rejection in 77 patients under primary cyclosporine (CyA)-based immunosuppression, in whom we reported a 74% salvage rate with a l3.9-month followup.2 To evaluate the longevity of the observed effects of tacrolimus rescue, we herein present a report and the long-term follow-up of this group of patients. Between July 14, 1989 and April 16. 1993. 77 patients (44 male, 33 female) with a mean age of 33.3 ± 12.4 years (range 2 to 59 years) failing CyA-based immunosuppression were converted to tacrolimus. Fifty-nine patients (77%) were primary transplant recipients and 18 (23%) had been retransplanted. Fifty-two patients (68%) were recipients of cadaveric grafts and 25 (32%) live donor grafts. All patients considered for tacrolimus conversion had uncontrolled biopsy-proven rejection. Previous antirejection therapy had been administered to all 77 patients in the form of bolus high-dose corticosteroids and 61 (79%) had also received at least one course of an antilymphocyte preparation. Tacrolimus was given at a standard daily dose of 0.3 mglkgld in divided doses every 12 hours starting 12 hours after the last CvA dose. Statistical significance was calculated by Studenfs'{ test or chi-square analysis as appropriate. Successful tacrolimus conversion was defined as a return to baseline serum creatinine (sCr), and/or improvement on postconversion renal allograft biopsy, and/or freedom from dialysis if the patient wa; dialysis dependent at the time of conversion. In our initial report on these 77 patients. we reported successful allograft salvage with tacrolimus conversion in 57 of 77 patients (74%) with a follow-up of 13.9 ± 9.1 months (range 2 to 34 months).2 Of the 57 patients whose grafts were successfully rescued initially. 41'1 (84%) continue to have functioning grafts with a mean sCr of 2.1 ± 0.85 mgldL at a mean follow-up of 41. 9 ± 12.1 months (range 16 to 62 months). There have heen nine late graft losses due to patient death (n = 3; two patients with functioning grafts and I with unknown allograft function). chronic rejection (n = 5). and patient noncompliance (n = I). Of the 18 patients on dialysis at the time of conversion. 9 (50ey). continue to have functioning grafts with a mean sCr of 2.1 mgldL (mean follOW-lip 45.1 ;: 11.9 months). In 61 patients who had received antilymphocytc preparations .. .19 (04r:r) continue to have functioning

Despite the improved results seen in renal transplantation observed with the introduction of cyclosporine (CyA) immunosuppression in the 1980’s, a finite number of grafts are still lost due to irreversible and ongoing rejection (1–3). Although the use of sequential induction therapy with antilymphocyte preparations followed by CyA mitigates the incidence of initial first rejection episodes to a certain extent, even retreatment with high dose steroids and/or further anti-lymphocyte therapy may be unsuccessful (4–6). These observations in clinical renal transplantation have stimulated interest in the development of novel drugs that may be useful in “rescuing” renal allografts failing these standard protocols. Tacrolimus is a novel macrolide immunosuppressant which has been used with encouraging results in primary renal transplantation (7, 8). This drug appears to have the additional advantage of permitting the tapering, and in some cases, cessation of steroid therapy allowing for tacrolimus monotherapy in up to 40% of patients (8). The efficacy of tacrolimus in primary renal transplantation led us to evaluate this agent for “rescue” of renal allografts undergoing intractable acute rejection which could not be reversed by the standard therapies available, including high dose steroids and antilymphocyte preparations (9, 10). This report summarizes our experience with tacrolimus for salvage therapy of rejecting renal allografts under primary CyA immunosuppression.