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NDT Advance Access originally published online on November 15, 2005
Nephrology Dialysis Transplantation 2006 21(1):36-39; doi:10.1093/ndt/gfi277
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© The Author [2005]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Dialysis and Transplantation News

Renal transplantation in Slovenia after joining Eurotransplant

Aljosa Kandus, Miha Arnol and Andrej F. Bren

Department of Nephrology, University Medical Centre Ljubljana, Ljubljana, Slovenia

Correspondence and offprint requests to: Prof. Aljosa Kandus, MD, PhD, University Medical Centre Ljubljana, Department of Nephrology, Zaloska 7, 1000 Ljubljana, Slovenia. Email: aljosa.kandus{at}guest.arnes.si



   Abstract
Top
 Abstract
Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. This report presents data on renal transplantation in Slovenia before and after joining Eurotransplant (ET).

Methods. Slovenia (population: 2 million) has one renal transplant centre. The establishment of an appropriate national transplantation organization resulted in an increase in transplantations and the acceptance of Slovenia into ET at the beginning of 2000. Current immunosuppression is composed of cyclosporin (Neoral®), mycophenolate mofetil, methylprednisolone and anti-interleukin-2 receptor monoclonal antibodies.

Results. By the end of 2004, 607 renal transplantations had been performed. From 1970 to 1998, 124 patients were given living related donor kidneys. From 1986 to 1999, 239 patients received renal grafts from deceased donors. From 2000 to 2004, 244 patients were transplanted from deceased donors. In 2004, 55 renal transplantations were carried out. One hundred and forty one (57.8%) renal grafts were shipped from other ET countries. The HLA–antigen mismatch of 2.8±1.1 was not significantly different from what it was before 2000. Up to 31 December 2004, the 1- and 3-year patient survival rates were 98.3% and 96.0%, respectively. The concomitant graft survival rates were 95.8% and 93.5%, respectively.

Conclusions. In the ET era, the number of deceased donor renal transplants per year was 2.8 times higher than in the 14 years before. In 2004, we reached the average number of deceased donor renal transplants per million population of ET. Although tissue compatibility in these recipients was not significantly better than it was before the ET era, it would have been much worse had we not joined ET. Short- and medium-term results in the ET era have been entirely comparable to those in large reports.

Keywords: graft survival; immunosuppression; patient survival; renal transplantation



   Introduction
Top
 Abstract
 Introduction
Subjects and methods
 Results
 Discussion
 References
 
Transplantation is the treatment of choice for a patient with end-stage renal disease [1]. It was demonstrated that long-term survival rates were better for renal transplant recipients than for wait-listed dialysis patients [2,3]. The recipients of successful renal transplants have a better quality of life than patients undergoing dialysis treatment [4]. In the United States, successful renal transplantation is more cost effective than haemodialysis and provides relative net savings after a period of ~3 years [5]. These advantages strongly support the development of renal transplantation.

In this article we present information on the methodology used in renal transplantation in Slovenia, our results in comparison with those of some other countries and the problems hindering transplantation in Slovenia. The results of the last 5-year period after joining Eurotransplant (ET) are presented in more detail.



   Subjects and methods
Top
 Abstract
 Introduction
 Subjects and methods
Results
 Discussion
 References
 
End-stage renal failure patients without significant accompanying diseases are appropriate transplant candidates. In February 2005, the formal upper age limit of 65 years for our renal transplant candidates was abolished. At the same time, the age limits of deceased kidney donors were changed from 60 to 65 years.

In Slovenia, which has an area of 20 000 km2 and a population of 2 million, there is one renal transplant centre located at the University Medical Centre Ljubljana and one tissue-typing centre at the Blood Transfusion Centre of Slovenia, also located in Ljubljana. Besides the University Medical Centre, nine donor hospitals have been included in the national programme for deceased donor kidney transplantation since 1998 [6]. The national renal waiting list is managed by the nephrologists of the University Medical Centre. The work-up of renal transplant candidates is performed in co-operation with nephrologists in regional dialysis centres following a uniform work-up protocol. The establishment of an appropriate national transplantation organization composed of a renal transplant centre, donor centres, a tissue-typing centre, a national waiting list and a central coordinating institution – Slovenija-Transplant – resulted in an increase in transplantations and the acceptance of Slovenia into ET, followed by the implementation of activities at the beginning of 2000.

On 21 January 2000, a new law governing transplantation activities was passed in Slovenia. In the case of deceased donors, informed consent was obtained regularly from donor relatives. All recipients were treated in the intensive care unit until post-transplant day 2 and were subsequently transferred to the hospital unit of the Department of Nephrology if no major problem existed. After discharge, the recipients are regularly monitored in the transplant outpatient unit of our department.

Prophylactic immunosuppression directed by nephrologists has changed over a period of >30 years. In the 1970s, patients were treated with azathioprine and steroids. Since 1986, all recipients were given cyclosporin, regularly combined with diltiazem, from the day of transplantation. In 1994, patients were switched to cyclosporin (Neoral®). All patients received steroids with cyclosporin and for 2 weeks after transplantation, azathioprine also. This drug was reintroduced after successful treatment of acute rejection. Since 1997, mycophenolate mofetil has been used as an adjunctive agent with cyclosporin (Neoral®) in selected patients. In October 1999, immunosuppression therapy was remarkably transformed; patients received basiliximab, a reduced dose of cyclosporin (Neoral®), a reduced dose of methylprednisolone and a standard dose of mycophenolate mofetil [7]. Since June 2002, patients have been randomized to induction with daclizumab or basiliximab. Some patients with cyclosporin side-effects (mostly cosmetic) were converted to tacrolimus. In selected patients with steroid side-effects, methylprednisolone was gradually withdrawn, but not before 6 months after transplantation. All treated acute rejections were confirmed by percutaneous renal graft biopsy.

Unless otherwise stated, the presented data are expressed as means±SD. Significance was assessed with the t-test for unpaired data. Patient and graft survival were calculated using the Kaplan–Meier technique. We also tried to assess the quality of life (QOL) by the aid of our own questionnaire. The participating patients graded, using a score from 1 (very bad) to 5 (excellent), their QOL with a transplanted kidney and during previous dialysis treatment. Comparison between both treatment methods was calculated using the t-test for paired data.



   Results
Top
 Abstract
 Introduction
 Subjects and methods
 Results
Discussion
 References
 
By the end of 2004, 607 renal transplantations had been performed in Slovenia. The first kidney transplant from a living related donor was performed in 1970 and the last in 1998. In this period, 124 patients (88 men and 36 women), aged 6–53 years, were given living related donor kidneys; 90 recipients were from our country, the remaining 34 were from other republics of the former Yugoslavia. The living related donors, aged 23–79 years, were parents (n = 91), siblings (n = 31) and grandparents (n = 2). The maximum number of such transplantations per year is 23, performed in 1986.

Regular deceased donor renal transplantation was begun in 1986. Until 31 December 1999, 239 patients (135 men and 104 women), aged 9–65 years, received renal grafts from deceased donors.

Since Slovenia joined ET at the beginning of 2000 through December 2004, 244 patients (139 men and 105 women), aged 46±11 years (range: 13–66 years), have been given renal grafts from deceased donors. The transplantation of a kidney recovered from a non-heart-beating donor has not yet been performed. Two hundred and twenty three (91.4%) patients had transplantations for the first time, while 21 (8.6%) underwent their second transplantation. One hundred and forty-one (57.8%) renal grafts were shipped from other ET countries, while the remaining 103 (42.2%) grafts were of local origin. Donor age was 37±14 years (range: 6–60 years). The HLA–antigen mismatch of 2.8±1.1 (range: 0–5) was not significantly different than the mismatch of 3.0±0.9 in deceased donor graft recipients before 2000. The median value of the latest panel-reactive antibody was 4% (range: 0–88%). The cold ischaemia time was 21.5±7.5 h. The time of 18.0±7.5 h (range: 7.0–41.0 h) was significantly shorter (P<0.01) in the recipients of local grafts than the cold ischaemia time of 24.0±6.0 h (range: 12.5–40.0 h) in the recipients of shipped grafts. Before 2000, a cold ischaemia time of 18.0±7.0 h was similar to that of local graft recipients of the ET era. Seventy-three (29.9%) patients experienced delayed graft function, defined as the need for dialysis in the first post-transplant week. Steroids were withdrawn gradually in 84 (34.4%) recipients. Most of them were included in the Steroid Withdrawal Project of the Collaborative Transplant Study [8].

Since Slovenia joined ET, acute rejection has been confirmed in no more than 15 (6.1%) recipients and successfully treated in 13 of them. In the first 3 post-transplant years, 14 renal grafts were lost. The causes of graft loss were as follows: early renal vein or artery thrombosis (n = 6), death of patient (n = 4), acute rejection (n = 2) and septic shock (n = 1). One renal graft with excellent function was removed on day 10 because of a metastatic bronchial carcinoma detected during the donor's autopsy. In the same period, seven recipients died: four in the first year (one with functioning graft) and the remaining three (all with functioning graft) in the third year. Up to 31 December 2004, the 1-year and 3-year patient survival rates were 98.3% and 96.0%, respectively. The concomitant graft survival rates were 95.8% and 93.5%, respectively.

From 1997 to 2000, the 1-year and 3-year deceased donor graft survival rates were 90.5% and 88.1%, respectively. From 1986 to 1996, the survival rates were 71.9% and 69.6%, respectively.

One hundred and thirteen adult recipients (62 men and 51 women) participated in the QOL questionnaire. Most of them were in the second post-transplant year. The QOL scores with transplanted kidney and during previous dialysis treatment were 3.97±0.74 and 2.67±0.83, respectively (P<0.001).

In 2004, the estimated cost of an uneventful deceased donor renal transplantation was {euro}46 000 by the end of the first year. Thereafter, the estimated annual cost was about {euro}7000. The annual cost for a patient undergoing chronic haemodialysis was about {euro}26 000.

At the end of 1999, there were 1128 chronic dialysis patients in Slovenia; 135 (12.0%) of them were on the national kidney waiting list. On 31 December 2004, 108 (8.2%) of 1325 chronic dialysis patients were included in the kidney waiting list.

On 31 December 2004, 418 renal graft recipients were registered at the transplant outpatient unit of the Department of Nephrology. A year earlier, there were 374 recipients. The great majority of these patients received transplants in our country.



   Discussion
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
References
 
In 2003, there were 66 renal transplant centres in ET countries (population: 119 million), on average one centre per population of 1.8 million [9]. This fact is in support of our conviction that one centre with a central geographic position is sufficient for a small country like Slovenia. Our association with ET offered several advantages. Because Slovenia is a small country, it is impossible to find a recipient of appropriate tissue compatibility for each procured deceased donor kidney [10]. Although tissue compatibility in deceased renal graft recipients was not significantly better than it was before 2000, it would have been much worse had we not joined the great community of ET. It should be noted that the total number of deceased donor renal transplants in the last 5 years was almost equal to the number of such transplants in the 14 years before 2000. This means a 2.8 times higher number of transplants per year in the last period. Furthermore, membership in a successful organization is a permanent incentive for keeping pace with the other members of such an organization. With 55 deceased donor renal transplants in 2002 and 2004, we reached the average number of these transplants per million population of ET in the last decade [9]. However, this achievement is still far from the most successful countries [11]. A shorter waiting time, the chance to give transplants to highly sensitized patients and of performing urgent transplantations are all further advantages of our association with ET. A prolonged cold ischaemia time affected many recipients, as it has well-known harmful effects [12,13]. This time could be reduced by improving transport from the procurement centre to the transplant centre, as well as by better organization inside our transplant centre. After the cold ischaemia time is shortened, there will be much less reluctance to accept kidneys from expanded criteria donors.

Our national waiting list per million population is almost three times smaller than the whole ET kidney waiting list per million population [9]. Moreover, it has become progressively shorter in the last decade. We believe that the small national waiting list is, at the moment, the main reason for the stagnation of deceased donor renal transplantation in our country. In the last year, kidney donations exceeded the number of transplantations by 20% [14]. Besides insufficient information to patients and rigorous inclusion criteria, the meticulous and slow work-up of candidates has also hindered the enlargement of the waiting list.

The number of living related transplantations per year declined after 1986. The expected increase in deceased donor transplantations could, at least partly, explain this decline. However, the increase of such transplantations did not occur until the establishment of an appropriate national transplantation organization in 1998. In spite of the slow growth of living donor transplantations in ET since the mid-1990s and the important contribution of these transplantations to the total transplant number in several north-western European countries and the USA, we do not believe in the revitalization of the living donor transplantation programme as long as the number of deceased donor transplantations is stable or higher, the waiting list is unchanged and the waiting time relatively short [9,11].

According to Slovene legislation, all recipients have to be under the medical control of a transplant institution. The implementation of this obligation is being progressively jeopardized due to inadequate conditions (the lack of patient care space, skilled personnel and equipment) in hospital and outpatient units accompanying the increasing number of recipients.

Since Slovenia joined the ET in January 2000, the short- and medium-term results of renal transplantation in our country, assessed on the basis of patient and graft survival, have been very good and are much better than in the past and entirely comparable to those presented in large reports [15, Collaborative Transplant Study (archive CTS-K-14101-0205, CTS-K-14102-0205) available at http://www.ctstransplant.org/]. These good results are most probably a reflection of effective and safe immunosuppression, the previous age limits of recipients and donors, as well as the careful overall treatment of patients before and after transplantation. The waiting list should be enlarged and the number of deceased donor donations increased in order to achieve a further increase in the number of transplantations. The improvement of conditions in hospital and outpatient units for the treatment of transplanted patients is needed urgently if we are to maintain the currently very good results.

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

  1. Kasiske BL. The evaluation of prospective renal transplant recipients. In: Greenberg A, ed. Primer on Kidney Diseases, 3rd edn. Academic Press, San Diego, 2001; 455–460
  2. Wolfe RA, Ashby VB, Milford EL et al. Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. N Engl J Med 1999; 341: 1725–1730[Abstract/Free Full Text]
  3. Ojo AO, Hanson JA, Meier-Kriesche H-U et al. Survival in recipients of marginal cadaveric donor kidneys compared with other recipients and wait-listed transplant candidates. J Am Soc Nephrol 2001; 12: 589–597[Abstract/Free Full Text]
  4. Goodman WG, Danovitch GM. Options for patients with kidney failure. In: Danovitch GM, ed. Handbook of Kidney Transplantation, 4th edn. Lippincott Williams & Wilkins, Philadelphia: 2005; 1–22
  5. Gaston RS, Gitlin MH. Psychosocial and financial aspects of transplantation. In: Danovitch GM, ed. Handbook of Kidney Transplantation, 4th edn. Lippincott Williams & Wilkins, Philadelphia: 2005; 495–504
  6. Voncina J. Transplant activities in Slovenia. Organs Tissues 1999; 2: 115–117[CrossRef]
  7. Kandus A. Preventing acute rejection with basiliximab and triple immunosuppression after renal transplantation. Transplant Proc 2002; 34: 2907–2909[Medline]
  8. Opelz G, Döhler B, Laux G. Long-term prospective study of steroid withdrawal in kidney and heart transplant recipients. Am J Transplant 2005; 5: 720–728[CrossRef][Web of Science][Medline]
  9. Cohen B, Persijn GG. Eurotransplant International Foundation Annual Report 2003. CIP-Gegevens Koninklijke Bibliotheek, Den Haag, 2003; 6–33
  10. Hunsicker LG. Renal transplantation for the nephrologist: HLA matching and cadaveric kidney allocation. Am J Kidney Dis 1989; 13: 438–441[Medline]
  11. Council of Europe. International data on organ donation, transplantation, waiting list and family refusals, year 2003. Newsletter Transplant 2004; 9: 17–24
  12. Amend WJC,Jr, Vincenti F, Tolmanovich SJ. The first three posttransplant months. In: Danovitch GM, ed. Handbook of Kidney Transplantation, 4th edn. Lippincott Williams & Wilkins, Philadelphia: 2005; 212–233
  13. Sahadevan M, Kasiske BL. Long-term posttransplant management and complications. In: Danovitch GM, ed. Handbook of Kidney Transplantation, 4th edn. Lippincott Williams & Wilkins, Philadelphia: 2005; 234–278
  14. Cohen B. Statistics. Eurotransplant Newsletter 2005; 198: 2
  15. Cardillo M, Poli F, Barraco F et al. Renal transplantation. Contrib Nephrol 2005; 146: 1–10[Medline]
Received for publication: 4. 8.05
Accepted in revised form: 25.10.05


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