Liver transplantation (LT) is the sole treatment modality of most of diffuse liver diseases. Simultaneous-pancreas-kidney (SPK) transplantation is also a life saving operation for IDDM patients. Both procedures are established treatment options in the European Community (EC) and in the US. These procedures are performed in a significantly smaller number in Hungary. Having a larger demand for LT than the supply of cadaver donors alternative solutions are sought to increase the number of transplantable livers. In Hungary partly the shortage of donors and the shortage of recipients are the factors rendering the number of LTs and SPKs low. These factors can be changed by better organisation and good survival data that make the two procedures accepted by the community of physicians

Kalmár Nagy, K.

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Acta Physiologica Hungarica, Volume 88 (1),  pp.  15–24  (2001)Liver and pancreas transplantationin Europe – and in Hungary*K. Kalmár NagyDepartment of Surgery, Faculty of Medicine, Pécs University, HungaryReceived: February 2, 2001Accepted: June 10, 2001Liver transplantation (LT) is the sole treatment modality of most of diffuse liver diseases.Simultaneous-pancreas-kidney (SPK) transplantation is also a life saving operation for IDDMpatients. Both procedures are established treatment options in the European Community (EC) andin the US. These procedures are performed in a significantly smaller number in Hungary. Havinga larger demand for LT than the supply of cadaver donors alternative solutions are sought toincrease the number of transplantable livers.In Hungary partly the shortage of donors and the shortage of recipients are the factorsrendering the number of LTs and SPKs low. These factors can be changed by better organisationand good survival data that make the two procedures accepted by the community of physicians.Keywords: Simultaneous-pancreas-kidney (SPK) transplantation, liver transplantation,cadaver donorsIn the sixties of the twentieths century renal transplantation became an establishedtreatment of end stage renal disease. At that time Hungarian surgeons and physicianskept up with the front line of the world. The first Hungarian renal transplant wasperformed by András Németh in 1963. It needed further thirty years for the liver and thepancreas transplant to become an established treatment modality.Liver transplantation became a routine procedure only during the past decadewith a result of 90% one-year survival rate at the best performing transplant centres.                                                          Correspondence should be addressed toK. Kalmár NagyDepartment of Surgery, Faculty of Medicine, Pécs UniversityH-7634 Pécs, Ifjúság u. 13, Hungary* The paper was presented at the Scientific Meeting of the Pécs and Veszprém RegionalCommittees of the Hungarian Academy of Sciences, November 4, 2000, Pécs, Hungary0231–424X/2001/$ 5.00 © 2001 Akadémiai Kiadó, Budapest16 K. Kalmár NagyNo other treatment of diffuse liver diseases in the given stage can provide betteroutcome. The same improvement goes to pancreas transplantation with 90% one-yearpatient survival and 80% one-year graft survival (12).The encouraging results of LT increase the demand for it while the resources oftransplantable livers remain limited. As most of LTs is performed from cadaver donors,the cadaver donor rate (i.e. the number of donors per million population per year) is oneof the main indicators of transplantation activity (Fig. 1).Due to different reasons not all the otherwise transplantable organs aretransplanted from a given donor. Those donors from whom more than one organ,usually kidneys, is procured are quoted as multi-organ donors. The proportion of multi-organ donors vary in different European countries (Fig. 2).The development of new immunosuppressive drugs, the improvement oftechnology in surgery and anaesthesia (2) and also the improving global exchange ofFig. 1. Cadaveric donors 1999 (per million population)Acta Physiologica Hungarica 88, 2001Liver and pancreas transplantation 17Fig. 2. Multi-organ donors 1999 (%)information in the field of transplantation had turned liver and pancreas transplantationfrom an experimental stage into routine. More and more physicians suggest this kind oftreatment to their patients. It was in 1994 when the demand for livers outnumbered thesupply in the United States. The means of meeting the rapidly growing demand fortransplantable organs are the following– Increase the number of brain dead cadaver donors by better organisation.– Transplantation of parts of non-paired organs from living donors.– Splitting the liver of a cadaver donor allowing two liver transplants from one donor.– Transplantation of organs from so-called non-heart-beating donors.The number of cadaver donors in a given country is determined by many factors,such as cultural, legal and historical. The cadaver donor activity also reflects thepreferences of the health government. The authorities in Spain and Austria put hugeeffort into the support of organ procurement programs. The result of it is clearly seen inActa Physiologica Hungarica 88, 200118 K. Kalmár Nagythe statistical data. The main principles of the “Spanish model” are being adopted inmany countries. One basic idea of the model is close cooperation between donorhospitals and the organ retrieving centres within a nationwide organization. A localtransplant coordinator is employed in every hospital either part-time or full-time infavour of salvage most of the transplantable organs. These coordinators seek and followevery potential donor in the hospital and in case of brain death of a patient theycoordinate the process of organ procurement. The specially trained coordinator is theperson who contacts the relatives of the deceased potential donor and obtains theconsent for organ donation (11). It can be also a promotional factor that the coordinatorovertakes the task of donor conditioning from the ICU staff who had fought for the lifeof the patient before the brain death happened. Donor conditioning is a special medicalskill of preservation of viability and function of the organs to be transplanted what isdifferent of the intensive care of the patient. Proper donor conditioning is pivotal for thehigh rate of multi-organ donation. It can be also a psychological relief to the ICU staffnot to be directly involved in organ donation.Though the criteria of declaration of brain or brainstem death are acceptedworldwide the legal rules of organ donation from a cadaver donor is different in manycountries. The most significant difference is whether the principle of informed consentor the principle of presumed consent is applied by the legal system. The appliance of thefirst mentioned one, in other words the opting in principle means the deceased personshould have permitted in his life the organ retrieval for transplant purposes or the nextof kin to the deceased has to consent it. The principle of opting out or presumed consentmeans that every person can object any organ removal for the case of his or her death,but the lack of written or orally given objection allows the presumption of consent fororgan donation.The result of a good organ procurement organisation and the application of optingout principle can be seen in the high donation rate in Austria (Fig. 1).The increasing demand for transplantable livers led to the development of thetechnique of LT from living donor. As the liver regains almost entirely its volumefollowing a resection, one-third or half of it can be removed safely for transplantation.Most commonly segments II-III or segments II-III-IV are removed for transplantation.On rear occasions the right half of the liver (segments V-VI-VII-VIII) is removed andtransplanted (9). Due to cultural and traditional reasons the public opinion in Japan doesnot recognise brain death and refuse organ transplantation from cadaver donor.Therefore overwhelming majority of LTs in Japan is performed from living donors.The experience with LT-s from living donors promoted split liver transplantationfrom cadaver donors. The process of splitting can take place either following theremoval from the donor in cold temperature or during the harvest procedure withsustained blood circulation (3). This latter method seems to be more promising withActa Physiologica Hungarica 88, 2001Liver and pancreas transplantation 19regard to the primary function of the transplanted halves of the liver (13). Split livertransplantation can theoretically double the number of liver transplants at the samenumber of cadaver donors.Another theoretical possibility of expansion of the donor pool is livertransplantation from non-heart-beating donors. In brain-dead cadavers the circulationand the blood supply of the transplantable organs is not compromised while in non-heart-beating cadavers the circulation had also collapsed and a compromised bloodsupply is provided only by external cardiac massage until preservation with coldsolution takes place. A few specialised transplant centres publish encouraging long-termresults of non-heart-beating renal transplants in spite of extremely high delayed-graft-function rate (5, 10). The research into the problems of liver transplantation from non-heart-beating donors is promising although there are only sporadic publications in theliterature on liver transplants from non-heart-beating donors. For the time being theprobability unacceptably high primary non-function rate seems to be prohibitive to livertransplant from non-heart-beating donors.In some liver transplant centres other means of optimal utilization of the limitednumber of cadaver donor livers are accepted. As the patient survival rate following livertransplant for primary hepatocellular or cholangiocellular cancer is the same as it isfollowing hepatic resection (8) liver transplant is only very cautiously indicated inprimary malignancies not associated with cirrhosis.In cases of liver failure caused either by primary non-function or any other reasonthe only chance of survival for the patient can be provided by retransplant within a fewdays. However the survival rate following such a liver transplant from a second donor isonly 50% versus 90% in first transplant cases. As patients can die on the waiting listwithout liver transplant, there are opinions that in favour of the optimal use of thetransplantable livers first liver transplants should be preferred over retransplants.The development of pancreas transplantation was not as straightforward as that ofthe liver transplantation. Before the widespread use of the new generationimmunosuppressive agents as Tacrolimus and mycophenyl mofetilate morecomplications were observed with an inferior survival rate (6). Only few centres kept onperforming pancreas transplants in that era. Most of them were American ones. Long-term experience of these established pancreas transplant programs show that the bestgraft survival rate is achieved by the simultaneous-pancreas-kidney (SPK) transplant.Therefore 95% of all pancreas transplants is SPK. According to the data of the UNOS(the United Network of Organ Sharing) the US transplant organization the death rate onthe SPK waiting list in 1996 was 7.47% per year whereas one-year patient survival rateof patients receiving SPK transplant in 1996 and 1997 is 94.1% expected five-yearsurvival is 81.9%(1). In other words SPK transplant provides better survival for IDDMpatients than kidney transplant alone (2).Acta Physiologica Hungarica 88, 200120 K. Kalmár NagyIt also seems to be out of mind that SPK transplant significantly improves thequality of life by making the patient insulin independent, euglycemic and free of dialysistreatment.It must be admitted however that even with the good results in survival andimproved quality of life pancreas transplantation remains the procedure with the highestcomplication rate among all solid organ transplants. It was in 1994 when the number ofpatients on both liver and SPK waiting list grown higher than the number of donors.Fig. 3. Liver donors and patients on the waiting list on the last day of the year (UNOS)Fig. 4. Pancreas donors and patients on the waiting list on the last day of the year (UNOS)Acta Physiologica Hungarica 88, 2001Liver and pancreas transplantation 21(Figs 3 and 4). In the author’s opinion 1994 was the year when the public opinion ofphysicians accepted liver and pancreas transplantation as a reliable, standard procedure.The state of transplantation in Hungary is comparable in some fields with theestablished western transplant programs. Results and activity of the four Hungarianrenal transplant programs are close to the European average. The Hungarian legal rulesof organ donation are in harmony with the legislation of more than half of the EuropeanCommunity countries adopting the “soft” opting out principle. As the Hungarian legalrules provide a good balance between the interests of the transplant recipient candidatesand the relatives of brain dead donors, the legislation cannot be named as cause ofdonor shortage. Some other reasons should be sought and found to explain why the dataof the Hungarian liver and pancreas transplant programs are inferior to the Europeanand American ones.The first Hungarian liver transplant was performed in 1985 by Andor Szécsény23 years after the world’s first. Since 1995 the sole liver transplant program run by theBudapest team performed more than 100 LTs. The 1999 liver transplantation activity ofa few voluntarily chosen countries can be seen in Figure 5.The first Hungarian pancreas transplant was performed at the author’s institutionin 1998 32 years after the first pancreas transplant in the world. The Pécs pancreasFig. 5. Liver transplants 1999 (per million population)Acta Physiologica Hungarica 88, 200122 K. Kalmár NagyFig. 6. Pancreas transplants 1999 (per million population)transplant program is the only one in Hungary for the time being. The program’sactivity is also behind the activity of the established western programs (Fig. 6).Eleven SPK transplants were performed during the past two years. Ten of them areinsulin independent with good renal function. One patient was lost on the 14thpostoperative day due to sepsis.Some more efforts are requested to obtain the same activity in liver and inpancreas transplantation as EC centres produce. Identification of those factors, whichshould be changed in favour of better performance, is of significant importance.The donor shortage in itself cannot be blamed for the poorer activity as most ofthe countries face the same donor shortage. Although every measure should be taken forthe increase of the donor pool hence such an increase might allow the choice of optimalorgans for transplant. Hungary has some resources to be more exploited, as there arehospital ICUs that never report cadaver donors. The adaptation of the aforementioned“Spanish model” might increase the number of donors and by standardisation of donorconditioning and organ procurement could improve the quality of transplantable organs.The shortage of recipients might be influential in the low activity. In some casesexcellent organs from cadaver donors are refused due to lack of recipient an the waitingActa Physiologica Hungarica 88, 2001Liver and pancreas transplantation 23list, rendering the rate of multi-organ donation low. About four thousands of patients diedue to diffuse liver diseases every year (4), but the number of patients on the livertransplant waiting list is rarely more than twenty. About 250 IDDM patients are inchronic haemodialysis program in Hungary and only 10 of them are on the pancreastransplant waiting list. The two transplant programs ought to produce and publishconvincing results that encourage physicians to put their patients on the lists.Another possible cause of low Hungarian multi-organ donation rate can be thatICU staff in some hospitals are not familiar with donor conditioning. Long hypotensiveperiods for instance can turn otherwise transplantable organs unusable. A well-organized organ procurement organization (OPO) might increase the multi-organdonation rate by providing help with donor conditioning.Financial burdens of liver and pancreas transplantation need not to be considered,as the budget provided for liver and pancreas transplants is regularly under spent.Certain changes in the policy of the health government might also promote liverand pancreas transplantation. Both programs are in monopolistic position with all of itspositive and negative consequences. Only a few European countries with relativelysmall population afford such monopoly in transplantation. For instance in Austria with 8million populations has three liver transplant programs. Setting up a second liver and asecond pancreas transplant program would generate a fruitful competition resulting inthe increase in number and improvement in quality.It can be concluded that no insurmountable obstacle renders the Hungarian liverand pancreas transplant activity relatively low. Every condition is given to reach in liverand pancreas transplantation the EC average. The planned Hungarian OPO –Hungarotransplant can provide better public control over transplantation and canincrease the public sympathy and altruism toward transplantation.REFERENCES1. 1999 Annual Report of the U.S. Scientific Registry of Transplant Recipients and the OrganProcurement and Transplantation Nerwork: Transplant Data 1989-1998. (2000, February 21).Rockville, MD and Richmond, VA: HHS/HRSA/OSP/DOT and UNOS. Retrieved (January 14,2000).2. Becker, B.N., Brazy, P.C., Becker, Y.T., Odorico, J.S., Pintar, T.J., Collins, B.H., Pirsch, J.D.,Leverson, G.E., Heisey, D.M., Sollinger, H.W.: Simultaneous pancreas-kidney transplantationreduces excess mortality in type 1 diabetic patients with end-stagerenal disease. Kidney-Int. 57,2129–2135 (2000).3. Busuttil, R.W., Goss, J.A.: Split liver transplantation. Ann-Surg. 229, 313–321 (1999).4. Fehér, J.: A májátültetés gondjai Magyarországon. (Problems of liver transplantation in Hungary.) Orv-Hetil., 137, 2355–2356 (1996).5. Hoshinaga, K., Shiroki, R., Fujita, T., Kanno, T., Naide, Y.: The fate of 359 renal allografts harvestedfrom non-heart beating cadaver donors at a single center. Clin-Transpl.: 32, 213–220 (1998).Acta Physiologica Hungarica 88, 200124 K. Kalmár Nagy6. Humar, A., Kandaswamy, R., Granger, D., Gruessner, R.W., Gruessner, A., Sutherland, D.E.R.:Decreased surgical risks of pancreas transplantation in the modern era. Ann. Surg., 231, 269–275(2000).7. International Figures on Organ donation and Transplantation activities 1999. Transplant Newsletter. 5,18–19 (2000).8. Iwatsuki, S., Starzl, T.E., Sheahan, D.G., Yokoyama, I., Demetris, A.J., Todo, S., Tzakis, A., VanThiel, D.H., Carr, B., Selby, R., Madriaga, J.: Hepatic resection versus transplantation forhepatocellular carcinoma, Ann. Surg. 214, 221–229 (1991).9. Johnston, T.D., Ranjan, D.: Extending liver transplantation: reduced-size-, split-, and living -donorgrafts. Hepatogastroenterology 45, 1391–1394 (1998).10. Kootstra, G., Kievit, J.K., Heineman, E.: The non heart-beating donor. Br-Med-Bull., 53, 844–853(1997).11. Matesanz, R., López Navidad, A. (1996): The transplant coordinator in Spain. In Organ donation fortransplantation, the Spanish Model. eds: Matesanz, R., Miranda, B., Grupo Aula Medica, Madrid,pp 57–66.12. Sollinger, H.W., Odorico, J.S., Knechtle, S.J., D’Alessandro, A.M., Kalayoglu, M., Pirsch, J.D.:Experience with 500 simultaneous pancreas-kidney transplants. Ann. Surg., 228, 284–296 (1998).13. Sommacale, D., Farges, O., Ettorre, G.M., Lebigot, P., Sauvanet, A., Marty, J., Durand, F., Belghiti, J.:In situ split liver transplantation for two adult recipients. Transplantation 69, 1005–1007 (2000).Acta Physiologica Hungarica 88, 2001

Liver and pancreas transplantation in Europe – and in Hungary

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Liver and pancreas transplantation in Europe – and in Hungary

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