A team of scientists of the Universitätsmedizin Berlin together with other 16 transplant centres in Germany and Switzerland has tested a new therapeutic immunosuppressive strategy, positively affecting the function of the kidneys after transplantation. The results of the investigation, which was a success, were published online in the journal The Lancet.

Since the first renal transplantation, rejection prevention and control have been main aims of medical research. While acute rejection rates have fallen to 10-15% at 1 year, chronic rejection still erode long-term transplant potential. Current drugs for prevention and treatment of renal rejection are remarkably improved with regard to their profile of effectiveness, but remain unsatisfactory in terms of safety.

Armamentarium of immunosuppressive agents used in transplantation is impressive. Therefore, it is important to optimise the treatment. Standard drug after kidney transplantation is ciclosporin, which binds to the cytosolic protein cyclophilin (immunophilin) of T-lymphocytes. This complex of ciclosporin and cyclophilin inhibits calcineurin, blocking NFAT activation, which is responsible for the transcription of interleukin 2. The function of ciclosporin can be observed in the early phases of the cell cycle (G0 and G1). Cyclosporin inhibits cellular and humoral immunological responses and modifies inflammatory reactions.

Another immunosuppressive agent is everolimus, which mechanism of action is based upon the inactivation of mTOR protein. It is effective especially in polytherapy. Many studies suggest that everolimus can affect the reasons for chronic allograft nephropathy development. In addition, it allows to reduce the dose of ciclosporin, blocks the vessels remodeling due to antiproliferative and proapoptotic properties. It is considered as less nephrotoxic in relation to ciclosporine. Moreover it has antiviral activity against CMV.

Scientists from the Charité ZEUS study proposed an immunosuppressive strategy to improve the function of transplanted kidney. The project enrolled 300 patients, aged 18 to 65, who undergone kidney transplantation. All of them received cyclosporin as a standard drug inhibiting inflammatory response. After 4 months from the transplantation studied population was divided into two groups. The first received medicines according to the protocol, without any change, the second group received in the protocol everolimus instead of ciclosporin. The key assessment was performed one year after the transplantation. It was found, that everolimus patients had the greatest advantages. Function of the transplanted kidney was significantly better in this group, compared to ciclosporin patients. Moreover, frequency of the acute rejection in everolimus group has not increased. Researchers believe that this results are very hopeful, however they add, that this is not an evidence of superiority of everolimus over ciclosporin. This will be assessed only after the long term observation of the patients. The future will show the best strategies.

Written by: Karolina Kłoda MD, PhD

Source:
1. Klemens Budde, Thomas Becker, Wolfgang Arns, Claudia Sommerer, Petra Reinke, Ute Eisenberger, Stefan Kramer, Wolfgang Fischer, Harald Gschaidmeier, Frank Pietruck. Everolimus-based, calcineurin-inhibitor-free regimen in recipients of de-novo kidney transplants: an open-label, randomised, controlled trial. The Lancet, 2011; DOI: 10.1016/S0140-6736(10)62318-5
2. Charité – Universitätsmedizin Berlin (2011, March 1). Improved outcomes following kidney transplantation. ScienceDaily. Retrieved August 8, 2011, from http://www.sciencedaily.com­ /releases/2011/03/110301091454.htm

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