Renal Allograft

Renal
Allograft

   

• 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.

  
  
  
    
  
  Editors’
  commentary:

  
   
  

   
  
  
  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.