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Current trends in allogeneic transplantation management


5 June, 2009  

Organ donation rates need to be increased beyond the current level across Europe to reduce organ trafficking, waiting times for transplants and deaths while on waiting lists. New biological drugs need to be developed

Ferdinand Muhlbacher Professor Department of Transplantation Medical University of Vienna Austria Board Member Eurotransplant International Foundation

Organ transplantation is in most instances a standardised, wellaccepted treatment for end-stage organ failure for the heart, lung, liver, kidney, small bowel, and, with different aspects, also for the pancreas. Transplantation has become the victim of its own success: high success rates create greater organ demand, which cannot be satisfied due to limited organ availability. Current strategies aim at improving donor availability and quality, and secondly at improving short- and long-term results by fine-tuning immunosuppressive protocols. Immunosuppressive effectiveness should be increased, but side-effects of immunosuppressive therapy and potential sequelae for the transplanted organs should be minimised. The ultimate goal is, of course, to induce donorspecific tolerance without long-term pharmacological immunosuppression, which is not reality yet.

Background

Organ transplantation has reached standard levels of medical treatment of end-stage organ failure over the last 10 years. Short- and longterm results have dramatically improved, with one-year graft and patient survival in the order of 70–90%, depending on the transplanted organ.[1] However, organ transplantation still suffers from two major problems: The increasing success stimulates an increasing demand for organs, which are simply not available, which in turn creates many problems. The waiting time for an organ is substantial – patients may die on the waiting list, not being allocated an organ within a suitable time. There are organ allocation and distribution justice discussions in society; commercial and/or illegal transplant activities in the third world; increasing live donation activities with additional donor risk; and also exclusion of patients from acceptance to a waiting list because their disease does not allow them to expect a long-term cure, although short-term improvement and palliation would definitely be possible.

The second issue is the need to maintain pharmacological tolerance for the patient’s lifetime to avoid organ rejection. This strategy not only is expensive but also has side-effects and carries various risks: susceptibility to specific infections, damage of the transplanted organ by the immunosuppressive drugs themselves, increased risk of developing de-novo  malignant diseases and, finally, limited organ function and development of a further episode of end-stage organ failure.

Critical issues in transplantation

The most critical issue in organ transplantation is donor and organ availability. Organ availability differs greatly in various European countries: for example, in Greece, but in Spain the number is 34.[2] Almost all European countries have differing transplant legislations and certainly also different organisational provisions for organ donation. Legally, there are two models that allow retrieval of organs from deceased donors: opting-in and opting-out solutions. In model 1, organs can only be retrieved if a potential donor has given consent during his/her lifetime or, as a modification, the next of kin decides on behalf of the deceased. The second model presumes that everyone is in favour of organ donation, unless he/she has rejected organ donation during life, or – again as a modification – the next of kin may put forward this objection on behalf of the deceased. Both models work in Europe in approximately a 1:1 distribution among the countries, but many variations make direct comparison of the models very difficult.

As far as organisational aspects are concerned, some countries have introduced a national transplant organisation (for example, UK Transplant in Great Britain; Agence Biomedicine in France; Deutsche Stiftung Organtransplantation in Germany). Some countries are organised in a supernational organ distribution organisation such as Eurotransplant, based in Holland, for the Benelux countries, Germany, Austria, Slovenia, and Croatia; or Scandiatransplant for the Scandinavian countries. The differences between healthcare systems in the European countries are reflected in the various organisational aspects of donation and transplantation
in all these EU Member States, and many attempts have been made to harmonise transplantation activities in Europe.

What are the challenges?

Long waiting times, death on the waiting list and organ trafficking – buying and selling of organs from live donors under doubtful conditions. Two international conferences, specifically aiming at donor protection, have defined conditions under which live donation in renal transplantation (Amsterdam Forum 2004)[3] and liver transplantation (Vancouver Forum 2005)[4] can be performed. These guidelines are accepted globally, with a few exceptions, but they do not improve donor availability. The European Union is currently developing a directive in which the legal framework of live and deceased donor donation should be regulated in principle, but this document will also contain advice on how donor availability can be improved.

The strategies suggested in these documents will be adopted from the successful models of the top European donor countries, such as Spain, Belgium, Portugal, France and Austria. The only successful strategy to fight organ trafficking is, of course, to provide sufficient transplantable organs within the appropriate time. The success of the EU activity will be estimated in the increasing number of organ donors in Europe. An EU-wide average donor number of 30 per million inhabitants per year is achievable if governments take this issue seriously and act accordingly by funding and structuring organ procurement systems.

The biological challenge

Success rates in organ transplantation are estimated in one- or five-year patient and graft survival times, and in the half-life time (time span after transplantation in which 50% of transplant patients are still alive with functional grafts). These data have continuously improved over the past two decades, and there is still a learning curve even within the past five years. Since surgical techniques have not changed dramatically, fine-tuning immunosuppressive strategies, as evidenced in many global multicentre trials, is apparently the key to success.

However, one-year patient and graft survival time seem to have reached a maximum of 90%, depending on the organ, but long-term survival is certainly not comparable to an age-matched normal population: the curves show a continuous decrease, which for kidney transplants is in the order of 3–5% graft loss per year. This phenomenon is commonly called chronic graft failure, and has slightly different morphological appearances in the various organs, but probably has one common denominator, which is an alteration of the vasculature resulting in graft fibrosis and disappearance of functional units (glomerula in the kidney, bile ducts in the liver) and leading to chronic organ dysfunction. Currently, it is totally unclear whether these phenomena are due to an unspecific inflammatory response to nonphysiological challenges during the transplantation period, (cold storage, hormonal influence during death), or whether these phenomena are the result of the continuous immunological challenge on a cellular or humoral level.

Finally, these phenomena may also be interpreted as side-effects of immunosuppressive therapy itself. Modern immunosuppressive protocols are tuned to take advantage of the immunosuppressive properties of various drugs in a synergistic manner, and to decrease side-effects of various drugs by minimising the dose.[5] The proof of a concept is  evidenced by the so-called learning curve.

Some side-effects, such as development of hypertension, diabetogenicity, neurotoxicity, haematopoetic depression and the unknown contribution of the development of de-novo malignancies, cannot be avoided. So it would be desirable to manipulate the recipient organism during the period of transplantation in such a way that the patient’s immune  system becomes tolerant to the donor organ but maintains the defensive capacities against microbiological agents and substances of other individuals or species. One strategy – the concept of microchimerism – has been shown to be very successful in this respect in experimental animals,[6] and the concept has also been shown to work in humans under specific conditions.[7,8] The challenge in these experiments is to decrease the side-effects, and the toxicity of the conditioning phase (perioperative manipulation to achieve tolerance) is outweighed by the benefit of long-term graft acceptance without immunosuppressive therapy.

As immunological tolerance on a broad scale is likely to be achieved in the near future, intermediate strategies are worth pursuing. The development of biological agents (monoclonal antibodies) to interact with immunological signalling at minimal or low-grade chronic toxicity is also a successful strategy.[9]

Conclusion

Every effort has to be made to increase donation rates beyond the level of 30 donors per million population per year, and this number should be an average number across Europe, not a peak value appearing in one or two countries. If this is achieved, organ trafficking, the detrimental length of waiting time for kidney transplants, for instance, and death on the waiting list will automatically decrease. To improve graft patency, the fine-tuning of current immunosuppressive protocols is successful. However, the development of new biological drugs to interact with immunological signalling and, as a long-term concept, the development of immunological specific tolerance to the donor organ will be the long-term goal of transplantation medicine.

References
1. Opelz G, Döhler B for the Collaborative Transplant Study.
Influence of time of acute rejection on long-term graft survival in renal transplantation. Transplantation 2008;85:661-6.
2. Ethics Committee of the Transplantation Society. The consensus statement of the Amsterdam Forum on the Care of the Live Kidney Donor. Transplantation 2004;79(4):491-2.
3. Delmonico FL. Vancouver forum on the live lung, liver, pancreas, and intestine donor. Transplantation 2006;82(9):1245.
4. Matesanz RE. International figures on organ donation and transplantation 2007. Newsletter Transplant 2008;13(1):1-52.
5. Ekberg H, Tedesco-Silva H, Demirbas A, et al. Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med 2007;357:2562-75.
6. Wekerle T, Kurtz J, Ito H, et al. Allogeneic bone marrow transplantation with co-stimulatory blockade induces
macrochimerism and tolerance without cytoreductive host treatment. Nat Med 2000;6(4):464-9.
7. Buhler LH, Spitzer TR, Sykes M, et al. Induction of kidney allograft tolerance after transient lymphohematopoietic
chimerism in patients with multiple myeloma and end-stage renal disease. Transplantation 2002;74(10):1405-9.
8. Kawai T, Cosimi AB, Spitzer TR, et al. HLA-mismatched renal transplantation without maintenance immunosuppression. N Engl J Med 2008;358(4):353-61.
9. Vincenti F, Larsen C, Durrbach A, et al. Costimulation blockade with belatacept in renal transplantation.
N Engl J Med 2005;353(8):770-81.