Efficacy of sirolimus compared with azathioprine for reduction of acute renal allograft rejection: a randomised multicentre study

doi:10.1016/S0140-6736(00)02480-6

The Lancet

Volume 356, Issue 9225, 15 July 2000, Pages 194-202

https://doi.org/10.1016/S0140-6736(00)02480-6 Get rights and content

Summary

Background

Acute rejection episodes after renal transplantation are an important clinical challenge, despite use of multidrug immunosuppressive regimens. We did a prospective, multicentre, randomised, double-blind trial to investigate the impact of the addition of sirolimus, compared with azathioprine, to a ciclosporin and prednisone regimen.

Methods

719 recipients of primary HLA-mismatched cadaveric or living-donor renal allografts who displayed initial graft function were randomly assigned, after transplantation, sirolimus 2 mg daily (n=284) or 5 mg daily (n=274), or azathioprine (n=161). We assessed the primary composite endpoint of efficacy failure, occurrence of biopsy-confirmed acute rejection episodes, graft loss, or death, and various secondary endpoints that characterise these episodes at 6 months and 12 months. Analyses were done by intention to treat.

Findings

The rate of efficacy failure at 6 months was lower in the two sirolimus groups (2 mg 18·7%, p=0·002; 5 mg 16·8%, p<0·001) than in the azathioprine group (32·3%). The frequency of biopsy-confirmed acute rejection episodes was also lower (2 mg 16·9%, p=0·002; 5 mg 12·0%, p<0·001; azathioprine 29·8%). At 12 months, survival was similar in all groups for grafts (97·2%, 96·0%, and 98·1%) and patients (94·7%, 92·7%, and 93·8%). 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 and related antibody treatment, compared with the azathioprine group. Rates of infection and malignant disorders were similar in all groups.

Interpretation

Use of sirolimus reduced occurrence and severity of biopsy-confirmed acute rejection episodes with no increase in complications. Further studies are needed to establish the optimum doses for the combined regimen.

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.

Section snippets

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 4×10^9/L or more, platelet counts of 100×10^9/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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ArticlesEfficacy of sirolimus compared with azathioprine for reduction of acute renal allograft rejection: a randomised multicentre study

Summary

Background

Methods

Findings

Interpretation

Introduction

Section snippets

Patients

Statistical analysis

Demographic characteristics

Discussion

Cell

Lancet

Kidney Int

Kidney Int

Kidney Int

Am J Kidney Dis

Lancet

Immunosuppressive strategies in transplantation

Lancet

Mycophenolate mofetil in renal allograft recipients: a pooled efficacy analysis of three randomized, double-blind, clinical studies in the prevention of rejection-The International Mycophenolate Mofetil Renal Transplant Study Groups

Transplantation

Mycophenolate mofetil for the prevention of acute rejection in primary cadaveric renal allograft recipients: U.S. Renal Transplant Mycophenolate Mofetil Study Group

Transplantation

The UNOS scientific renal transplant registry

Synergistic interactions of cyclosporine and rapamycin to inhibit immune performances of normal human peripheral blood lymphocytes in vitro

Transplantation

Nuclear association of a T cell transcription factor blocked by FK506 and cyclosporine A

Nature

RAPT1, a mammalian homolog of yeast TOR, interacts with the FKBP12/rapamycin complex

Proc Natl Acad Sci USA

Sirolimus (rapamycin)- based therapy in human renal transplantation: similar efficacy and different toxicity compared with cyclosporine

Transplantation

Immunosuppressive effects and safety of a sirolimus/cyclosporine combination regimen for renal transplantation

Transplantation

A Blinded, long-term, randomized multicenter study of mycophenolate mofetil in cadaveric renal transplantation

Transplantation

Articles
Efficacy of sirolimus compared with azathioprine for reduction of acute renal allograft rejection: a randomised multicentre study