Barry D Kahan for the Rapamune US Study.
Efficacy of sirolimus compared with azathioprine for reduction of acute renal allograft rejection: a randomized multicentre study.
The Lancet, vol.356, July 15, 2000, PG.194-201
Acute rejection episodes are an important clinical challenge in renal transplantation. Despite use of multidrug immunosuppressive regimens, 20-40% of recipients have these events, which increase health care costs and are an important risk factor for chronic allograft failure.
Members of Rapamune US study group did a prospective multicentre, randomized double blind trial to investigate the impact of addition of sirolimus (rapamycin), compared with azathioprine to a ciclosporin and prednisone regimen. Sirolimus was used in the dose of 2mg or 5mg daily. A total of 719 patients were studied.
The rate of efficacy failure at 6 months was lower in the 2 sirolimus (rapamycin) groups than in the azathioprine group. Patients on sirolimus showed a delay in the time to first acute rejection episode, and decreased frequency of moderate and severe histological grades of rejection episodes compared with azathioprine group. Rates of infection and malignant disorders were similar in all groups.
Interpretation of the study is that use of sirolimus reduced occurrence and severity of biopsy confirmed acute rejection episodes with no increase in complications. Further studies are needed to establish optimum doses for the combined regimen.
Kahan and colleagues found that patients with renal transplants on rapamycin plus ciclosporin had fewer episodes of acute rejection than did those on azathioprine and ciclosporin. However, impaired renal function, raised blood pressure, and hyperlipidaemia were commoner among patients in the rapamycin than in the azathioprine group. Each of these variables may reduce long-term survival of graft or patient. The increased susceptibility to nephrotoxicity and hypertension in the rapamycin groups seem to be due to a poorly understood interaction between rapamycin and ciclosporin that intensified the action of ciclosporin. This interaction also raises the possibility that some of the efficacy of rapamycin in the study may be attributable to enhancement of the effect of ciclosporin.
Although Kahan and co-workers’ study shows the efficacy of the combination, the prevalence of the side-effects suggests that their protocol is not the best way of using rapamycin. A reduction in the dose of ciclosporin may help but the efficacy of this change would require evaluation.