ArticlesEfficacy of sirolimus compared with azathioprine for reduction of acute renal allograft rejection: a randomised multicentre study
Introduction
Acute rejection episodes continue to present an important clinical challenge in renal transplantation. Despite the use of multidrug immunosuppressive regimens, 20–40% of recipients have these events, which increase health-care costs and probably represent an important risk factor for chronic allograft failure.1, 2, 3, 4.
In vitro and in-vivo studies suggest that sirolimus with ciclosporin act in a complementary way.5. Ciclosporin, a cyclic endecapeptide, inhibits the cytosolic enzyme calcineurin,6 which dephosphorylates critical intermediates after antigen-driven cell activation (signal 1), including the nuclear factor of activated T lymphocytes, a regulatory protein that promotes transcription of proinflammatory cytokine genes encoding interleukins 2, 4, 7, 9, and 15, and interferon gamma.7. The calcineurin inhibition is, however, only partial and is further mitigated by costimulation via the ciclosporin-resistant CD28 and CD 154 signal 2 pathways1. By contrast, sirolimus blocks a regulatory kinase that participates in transduction of signals delivered by CD28 and T-cell growth-factor receptors (signal 3).8 Although sirolimus monotherapy produces potent immunosuppression in animals,9 and combination with azathioprine and prednisone gives moderate rejection prophylaxis in human beings,10 more powerful, perhaps synergistic, effects are seen when the drug is combined with ciclosporin.5, 11 Therefore, we did a phase III multicentre, randomised, double-blind, pivotal trial of human renal transplantation to compare the potency of sirolimus with that of azathioprine in combination with a baseline ciclosporin microemulsion and prednisone regimen.
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Patients
Eligible patients had end-stage renal disease, were aged 13 years or older, and weighed at least 40 kg. Women of childbearing age with a negative pregnancy test before study medication was started were eligible. We required that patients had white blood cell counts of 4×109/L or more, platelet counts of 100×109/L or more, triglyceride concentrations of 5·65 mmol/L or less, and cholesterol of 9·05 mmol/L or less. We excluded patients who had evidence of systemic infection, angina, myocardial
Statistical analysis
Previous phase II multicentre studies showed an 18% rate of efficacy failure at 6 months for patients with sirolimus, ciclosporin, and prednisone17 and 36% for a group who received azathioprine, ciclosporin, and prednisone.12 We therefore calculated, by the method of Fleiss,18 that we would need sample sizes of 234 patients in each sirolimus group and 117 patients in the azathioprine group to show a significant difference in the endpoint between the results of unequal-sized groups and to
Demographic characteristics
719 patients were enrolled—284 were assigned sirolimus 2 mg daily, 274 sirolimus 5 mg daily, and 161 azathioprine (figure 1). In addition to the study-mandated stratification of black recipients, who comprised almost 25% of the whole study group, mean age, number of HLA mismatches, percentage panel-reactive antibody, height and weight, and primary causes of renal failure and donor source were similar in all three treatment groups (table 1). Most renal-allograft donors were white and were
Discussion
Sirolimus improved the immunosuppressive activity of a ciclosporin and prednisone regimen. Acute rejection episodes were significantly fewer, delayed in onset, and had less histopathological change and requirement for treatment with antilymphocyte antibodies. Rates of acute rejection episodes were similar to those seen in an earlier, single-blind, multicentre, international, phase II trial of sirolimus,17 despite multiple adverse demographic factors—23% of patients were black, average age was
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