Abstract
Nowadays artificial devices are not able to totally and undefinitely replace the loss of function of all vital organs and artificial organs can be used only to bridge the time to transplantation, which must be considered the first choice in the therapeutical approach for many chronic diseases. Since general population aging process is leading to an increase of organ demand, the gap between performed and requested transplantation is hard to fill. Xenotransplantation is nowadays only an experimental alternative solution and we have to do our best using available artificial organs to increase and improve the survival of patients waiting for transplantation. In this meeting we particularly dealt about organ function replacing therapy, especially regarding the kidney, heart, liver, pancreas and ear.
Introduction
Transplantation must be considered the first choice in the therapeutic approach for many chronic diseases. Nowadays there is no artificial device, which could totally replace the loss of function of vital organs like heart or liver. Only dialysis treatment can partially replace exocrine renal function, but accelerated atherosclerosis, osteodistrophy, amiloidosis, and other important pathologies continue to decrease the quality of life of dialyisis patients. Most artificial organs can only be used to bridge the time to transplantation but in the last years much progress has been achieved in developing artificial organs.
Transplantation in USA and Italy
The United Network for Organ Sharing ((UNOS)) reports the importance of Organ Sharing ((UNOS)): 74039 pts are waiting for transplant; the number of donors recovered in 1999 was 10576 and 21655 transplants have been performed in the same year. The Italian situation is well described by data from the Italian Society of Nephrology, showing an increasing transplantation activity in the years between 1990 and 2000 ((from 844 to 2468 transplants performed)) and a minor increase in donor organs ((from 289 to 788)). Moreover, the aging population, well described by Prof. Giampapa in his lecture, is leading to an impressive increase in the number of patients on waiting lists. Unfortunately the gap between organ demand and organs availability could hardly disappear because of the shortage of donor organs but, on the contrary, the increasing number of transplants seems not to be able to fulfil the increasing demand. Therefore, while waiting for alternative solutions, like xenotransplantation, we have to do our best using available artificial organs.
In this meeting we particularly dealt with therapies for replacing organ function, especially for kidney, heart, liver, pancreas and ear.
Kidney
It's well known that kidney was the first organ to be successfully replaced, at least as regards the exocrine function. From the primitive Kolff's artificial kidney, much subsequent amelioration has been achieved. For instance, as reported by Prof. Biagini, vitamin E coated dialysis membranes have been developed in order to decrease the oxidative stress, which seems to contribute to the worsening of uremic anemia, during dialytic sessions. Furthetmore, alternative dialytic techniques, such as AFB described by Dr. Atti, or HDF, HFR on line and CPFA described by Dr. Tetta, have been tested in order to improve dialyzed patients' quality of life and increase the efficacy of the treatment itself, thus leading to a decrease in total costs. Today, about 30000 pts are undergoing hemodialysis treatment in Italy, with a mean dialysis time of 12 hours per week while peritoneal dialysis, which has also recently achieved great progress, as reported by Dr. Brambilla, is performed by 10%% of pts, mostly at home. Patients' mean age is 60 years and their survival rate is slightly below the normal population's one, while their quality of life is certainly worse than the transplanted patients' one. Professor Bonomini, in collaboration with Prof. Stefoni, have been working for many years now on a model of Bionic Kidney designed to possess all renal functions. The development of such a device will be a real challenge in the new millennium. On the other hand, kidney transplants started the replacing surgery history, the first transplantation having been performed in 1954 by Murray in Boston on two monochorionic twins. The first transplantation in Italy was performed by Stefanini‐‐Cortesini‐‐Casciani in 1966. In 1997, the organ demand was for 2400 kidneys; 1210 organs were drawn from dead donors, 1190 transplantations from dead donors were performed, while 119 were performed from living donor; finally, 25 combined ((kidney–pancreas)) transplantations were performed. So, on the whole, 11 kidneys per million inhabitants were transplanted in 1997, the organ demand being 30 kidneys per million inhabitants.
Heart
Prof. Viganò and his group have studied the potentiality of different kinds of artificial devices, which can substitute cardiac damaged function, and reported a review from literature and his own experience. On December 2nd 1982, in Salt Lake City, the first artificial heart transplantation was performed. The heart–lung device was conceived in the XIX century and was also studied by Lindbergh, the lonely flyer. It consists of a peristaltic pump, to keep blood circulating, and of an oxygenation circuit. In 1963 it was introduced into the clinical practice and made the diffusion of the non‐‐beating‐‐heart surgery possible. The intra‐‐aortic balloon pump, also named “contro pulsator”, introduced in 1967, is a partial myocardial support device. It was Kolff, the inventor of the artificial kidney, the one who promoted the research to obtain an implantable artificial heart. This one was used for the first time by Cooley in 1969 as a bridge to transplantation, which was performed after 64 hours. The most famous artificial heart is Jarvik‐‐7, which allowed a patient to survive for more than 600 days of implantation. De Vries observed the longest survival period, which was 620 days long. As a matter of fact, many kinds of infection and embolic complications limited the use of the “Total Artificial Heart” ((TAH)). The last prototypes, created by the UPMC ((University of Pittsburg, McGowen Center)) are the Streamliner Artificial Heart and the Baxter Novacor. The so‐‐called “cardiomyoplasty”, introduced by Carpenter in 1985 is also worth of mention. It consists of wrapping the failing heart in the great dorsal muscle and stimulating it by a current injector. The first cardiac transplantation was performed by Barnard on December 2nd 1967 in Cape City; the first transplantation in Italy was performed on November 15th, 1985 in Padova. Nowadays there are precise clinical indications for cardia transplantation, which has gained valid clinical results. The Italian demand in 1997 was for 600 organs, with 377 hearts drawn from donors and 345 transplantations performed ((4 heart–lung transplantations)).
Liver
The attempt to replace liver function has not yet led to good results: dialysis, plasmapheresis, column perfusion and hybrid devices have been used separately or in association leading to sporadic good results. Nowadays, bioreactors made of porcine or human hepatocytes are under assessment. Professor Chamuleau proposes as an ideal solution for unsolved problems regarding bioreactors the use of well differentiated non‐‐tumorigenic human liver cells but successful development of sufficient amounts of such a kind of cells belongs to the future. On the other hand, the approach to liver transplantation is totally different from kidney tranplantation. The first orthotopic liver transplantation was performed in Denver in 1963 but reached real clinical uses only in the '80s. Today, the indications for liver transplantation are standardized and the survival rate is excellent. Transplantation from living donor is mostly performed in children but it may be used for adults, too: the left lobe, which can regenerate in a very short time, is drawn from the donor. In 1997, in Italy, the need for liver transplants required 600 organs; 466 livers were drawn from donors and 461 transplantations were performed.
Pancreas
The use of automatic injectors for insulin started the attempts to create an artificial pancreas. In pancreatic failure, the organ replacement is effective because it can be achieved by insulin administration only. Prof. Brunetti and his collaborators, particularly studied the possibility to create an artificial, miniaturized, implantable pancreas and the problems to be overcome in order to achieve this goal. Kelly and Sillehes in Minneapolis performed the first pancrea transplantation in 1966. Transplantation of single pancreas leads to poor results; combined kidney–pancreas transplantation is more commonly used and allows an earlier detection of rejection. Furthermore, Prof. Ricordi and his team are developing new techniques to perform isolated pancreatic islets transplantation. The need was for 150 organs in 1997 in Italy: 42 were drawn, no isolated transplant was performed and 25 combined transplantations were performed.
Ear
Deafness is a relevant social problem, which creates enormous barriers and difficulties in social interaction, especially in children. The bionic ear was particularly studied by Prof. Colletti and his equipe, with a case series of 124 implants: 50 performed by the retromastoid route and 71 by the subtemporal route, with 3 bilateral implants in the same surgical session. Furthermore, they applied 9 brainstem implants both in children and in adult patients.
Multi‐‐organ Transplantation
It has been performed more and more frequently, including bowel transplantation. Transplantation in abdominal metastasis is still under assessment ((Tzakis)). Bone marrow cells implantation could decrease rejection incidence.
Xenotransplantation
Started in the '60s and performed in Rome by Stefanini, Cortesini and Casciani in 1966, it still remains a large experimental field. Prof. Mosca well explained how the advances made in immunogenetics at the end of the twentieth century have allowed us to understand the molecular basis of rejection, and how the availability of new immunosuppressant drugs has renewed interest in the possibility of transplanting “non‐‐primate” animal organs in man. In this new perspective of using genetically more discordant species, pigs have taken on a pre‐‐eminent role insofar as they can be bred in large numbers and rapidly reach a size that is suitable for human transplantation, their physiology is similar to that of humans, and they probably present fewer risks in terms of transmittable diseases. Furthermore, as far as ethical considerations are concerned, it seems to be logical to assume that there is no substantial difference between sacrificing them for purposes of food and sacrificing them for life‐‐saving therapeutic purposes. It can therefore be hypothesised that only the minority of the population opposed to the killing of animals for any reason ((even as a source of food)) will not agree with their use as organ donors. Nevertheless, although these technical and ethical possibilities give rise to great hopes, it needs to be recognised that xenotransplantations between different species creates equally great fears concerning the risks for humankind as a whole that may be engendered by a violation of the between‐‐species biological barriers that have been built up over thousands of years. The infective agents of other species ((viruses, retroviruses, priones, etc.)) could adapt themselves to humans under facilitating conditions such as those induced by immunosuppression, which induces recipient tolerance to the xenotransplant itself but could also modify the susceptibility of the body to “non‐‐human” infections. It is worth remembering that xenotransplantation is only one means of compensating for the lack of transplantable human organs. The advances being made in the fields of basic science, biotechnology and bioengineering make it possible to imagine the use of in vitro tissue reconstruction in the near future, and possibly the use of stem cells to create healthy organs capable of replacing their diseased counterparts. Finally, even if it is capable of significantly contributing towards solving the problem, any therapeutic alternative to traditional transplantation should only be considered in the case of emergencies involving patients whose general conditions make them optimal transplant candidates.
Conclusions
An unquestionable success has been achieved in the field of organ replacement but there are still many unsolved problems. In conclusion we can say, following Professor Famulari's words, that current organ shortage is estimated to keep outpacing organ demand for years to come. Bionic organ science may be a valid option, allowing the bridging oif some patients on waiting list to transplantation. Kidney, liver, heart and lung can be transplanted with a long survival time. Xenotransplantation still remains an experimental approach. The real problem in transplantation is the availability of donor organs: this should be the goal of Health Planning in the future. However, concerns still exist regarding patient stratification and allocation criteria, timing and type of transplantation after organ recovery and long term risks of transmittable animal diseases and transfer of immunogenic molecules. Anyway, bioartificial organs should actually be regarded as a part of the wide armamentarium to offer patients with failing organ function.