Allocation of organs, particularly kidneys, within Eurotransplant.

Allocation of scarce donor organs is an important discussion topic among ethical, medical, and legal experts, the public at large, and politicians. Since 1996, a new kidney allocation system based on primarily medical and patient-oriented criteria was introduced in Eurotransplant (ET). This point-scoring system takes the following factors into account: HLA-A,B,DR mismatch, mismatch probability, waiting period, i.e., time on dialysis, distance between donor/transplantation center, and balance between import/export of the six participating countries. Extra points are given to high urgency patients and to children. During the first 9 years of the new ET kidney allocation system (ETKAS) almost 30,000 deceased donor kidneys have been allocated of which 22.3% have been transplanted without HLA-A,B,DR mismatches. Twice as many long-waiting patients, i.e., >5 years, have been transplanted as compared with the pre-ETKAS period. Also substantially more children and highly sensitized patients received kidney transplants. Importantly, the balances between import and export of donor kidneys among the different ET countries remained among very well-accepted levels. Finally, overall kidney transplant survival was 78% after 3 years and a significant HLA-matching effect was noticed, i.e., 83% at 3 years for the HLA-A,B,DR mismatched combinations. In conclusion, the new ETKAS has reached its aims and goals. The main problem remains, however, the continuing shortage of deceased donor kidneys.

Acceptance criteria of pancreas grafts: how do surgeons decide in Europe?

OBJECTIVES: Some donor factors, such as age, cause of death, and obesity, affect the outcomes of pancreas transplantation. Donors with a high-risk profile are usually not declined for pancreas donation. The purpose of our study was to investigate differences between accepted and refused pancreata after being procured and offered. METHODS: In a retrospective study we analyzed all offered pancreata (n = 1360) in the "Eurotransplant Area" between May 25, 2002 and September 18, 2003. Included in this study were 525 pancreata transplanted (38.6%) and 608 pancreata refused for medical reasons (44.7%). A total of 227 pancreata (16.7%) refused for other than medical reasons were excluded from this analysis. RESULTS: The significant differences in the donor profiles between transplanted and refused pancreata were cause of death (P < .001), donor age (P < .001), body mass index (BMI, P < .001), serum lipase and amylase (P < .05) at the time of procurement, and a history of smoking (P = .001) or alcohol abuse (P < .001). No differences were found for serum sodium (P = .188), blood leukocytes (P = .349), serum glucose at the time of procurement (P = .155), amylase and lipase at the time of admission (P = .34; P = .758), and vasopressor use at the time of admission or at the procedure (P = .802; P = .982). CONCLUSION: Even after procuring and offering potentially good pancreata, nearly half the organs are refused for medical reasons. Acceptance criteria in the Eurotransplant region reveal a conservative attitude toward pancreas acceptance.

Time trend in annual kidney graft survival.

First cadaver, unrelated kidney graft survival at one year from 50 Eurotransplant centers was analyzed and found to show marked changes in survival rates over the 20-year period from 1967 to 1986 inclusive. Full information on HLA-A, -B, and -DR matching and use of cyclosporine therapy was only available for the period 1981 to 1986. When these factors were allowed for, the number (and type) of HLA mismatches was shown to have a significant and independent effect on differences in survival rates whereas the effect of cyclosporine differed over the different years.

The significance of complete serological testing for hepatitis B in heart valve banking.

Allograft heart valves obtained from donor hearts have been cryopreserved in the Heart Valve Bank in Rotterdam for transplantation purposes. In contrast to hepatitis B screening of organ donors, which consists of only a rapid HBV surface antigen (HBsAg) assay, tissue donors can be screened more completely for hepatitis B virus (HBV) by HBsAg and antibodies against HBV core antigen (anti-HBc) tests, and when necessary, anti-HBs and HBV-DNA tests. The value of this complete HBV screening was investigated by evaluation of the HBV screening results of 676 donor sera. HBsAg was positive in 1 serum. Anti-HBc was positive in 63 sera, of which 52 also had positive antibodies against HBV surface antigen (anti-HBs) tests (no risk of transmission) and 10 had negative anti-HBs tests. In 3 cases with a negative anti-HBs test the HBV-DNA test was positive (risk of transmission). In 3 cases not enough serum was available to perform all tests, resulting in a total of 7 rejected donors. Single HBsAg testing would have resulted in the rejection of only 1 donor. In the presented group of selected donors, approximately 0.5% of the HBsAg-negative donors were lower-level chronic carriers of hepatitis B. Complete HBV screening decreases the risk of transmission of hepatitis B in allograft heart valve transplantation.

The impact of center variation on the HLA-DR matching effect in kidney graft survival.

Data from 7436 cases of first-cadaver transplants between 1981 and 1986 from 50 transplant follow-up centers within Eurotransplant, were analyzed with respect to the effect of HLA-DR matching on graft prognosis within the first year posttransplant. The use of cyclosporine was allowed for as well as the variation in graft survival rate between transplant follow-up centers. After adjustment for these variables, HLA-DR matching was still very significant. The effect of CsA on graft survival varied between centers--i.e., interaction was observed--but the effect of HLA-DR mismatching did not vary significantly between centers. Over all the centers there was a 1.4-fold increase in relative risk for each increase in HLA-DR mismatch, corresponding to predicted one-year graft survivals of 86.5%, 81.9%, and 75.4% for 0, 1, and 2 HLA-DR mismatches respectively, in patients receiving CsA, and 72.5%, 64.2%, and 53.6% in patients not receiving CsA.

The outcome of kidney grafts from multiorgan donors and kidney only donors.

From 1988 to 1994, 15356 renal cadaveric transplantations have been performed within the Eurotransplant area (Austria, Belgium, Germany, Luxembourg and The Netherlands); 8746 kidneys were obtained from multiorgan donors and 6610 from kidney only donors. To evaluate the impact of the procurement policy, multiorgan donor (MOD) versus kidney only donor (KOD), on renal graft survival, an observational study has been performed. Multivariate analysis using Cox's proportional hazards model served to quantify the role of the procurement policy on renal graft survival after adjustment for other prognostic factors. The kidneys obtained from MODs had a significantly better graft survival at 1, 3, and 5 years after transplantation than the kidneys obtained from KODs (85%, 75%, and 58% versus 78%, 68%, and 46% (P=0.0001). In the Cox model, patients transplanted with a KOD kidney had a 1.28 times higher risk of losing their graft than patients transplanted with a MOD kidney. This benefit in graft survival for MOD kidneys could not be explained by the fact that the MODs were younger and male, and that UW was used as preservation solution. A plausible explanation is that MODs, on average, because of the nonrenal transplants, are better supervised. We expect that optimal donor management will contribute to a better outcome of all renal grafts.

Influence of previous immunization on skin graft survival.

The results of skin grafts transplanted in immunized and nonimmunized recipients was analysed. Specific sensitization for HLA-A or B determinants shortens graft survival if the recipients were immunized by s.c. injections of leukocytes. When the recipients had been pregnant, no such influence of specific HLA-A or B sensitization could be demonstrated. The variance in mean survival times of grafts exchanged between mixed lymphocyte culture (MLC)-positive donor-recipient combinations was significantly smaller than the variance in mean survival time (MST) of grafts exchanged between MLC-negative combinations. This difference could be the result of the influence of allograft immune-activating determinants of different strength in the MLC-negative donor-recipient combinations. Also the variance in MST of grafts in immunized recipients was significantly larger than the variance in MST of grafts in nonimmunized recipients. Apart from the obvious effect of HLA-A and B sensitization, other less well documented factors must have influenced graft survival. We did not find evidence for a graft enhancing effect of B cell-specific antibodies.

Analysis of the renal transplant waiting list: application of a parametric competing risk method.

BACKGROUND: The strong competition for scarce renal graft resources jeopardizes an individual patient's chances of a transplantation within a reasonable time scale. This study was undertaken to quantify these chances of receiving a transplant. METHODS: All patients registered for their first renal allograft between January 1980 and December 1993 (n=40,636) in Eurotransplant were selected. The influence of patient characteristics, such as age, HLA phenotype frequency, % panel-reactive antibodies, period of registration, and ABO blood group, on the waiting list outflow was studied. The competing risk method was applied, and Poisson models were built to estimate the risk factor effects. RESULTS: The chance of transplantation within 10 years after registration was overestimated by Kaplan-Meier (84%); using the competing risk method it was only 74%. The predicted chance for death on the waiting list was overestimated by 33% (45% Kaplan-Meier vs. 12% competing risk). A time-varying covariate effect on the chances of waiting list outflow was observed. Favorable factors for quick transplantation, such as blood group AB or a common HLA phenotype, were no longer seen to be driving forces for transplantation once 5 to 6 years of waiting time had been accrued. CONCLUSION: When multiple outcomes exist, Kaplan-Meier estimates should not be interpreted as survival rates, while competing risk estimates yield appropriate chances. A significantly decaying effect of the usual allocation parameters is observed with ongoing waiting time. This phenomenon is the statistical basis for redesigning allocation strategies. Organ exchange algorithms should have the potential to adapt to these time-varying effects.

The new Eurotransplant Kidney Allocation System: report one year after implementation. Eurotransplant International Foundation.

BACKGROUND: Upon the availability of a cadaveric donor kidney, a delicate allocation process precedes every transplantation. A remodeled Eurotransplant Kidney Allocation System (ETKAS)-derived from simulation studies-was installed in March 1996. The purpose was to adjust long waiting times and international exchange balances, while aiming at an optimal HLA-mismatch distribution. The new ETKAS consisted of a point-score system that was 100% patient oriented. METHODS: The impact of the new ETKAS on the composition of the waiting list, and the outcome of the allocation procedures during its first year, were evaluated and compared with the results obtained in 1995. RESULTS: The percentage of long-waiting patients and of patients with poorly matchable HLA phenotype increased significantly, from 9% to 19% and from 19% to 29%, respectively. Zero HLA-A-, HLA-B-, HLA-DR-mismatched patients still comprised 23% of the kidney transplant activity. The kidney exchange of the different Eurotransplant countries became balanced within 4 months; this persisted during the rest of the year. Pediatric patients had a high transplantation rate due to an assignment of extra points. The composition of the waiting list showed, after 1 year, fewer long-waiting patients and fewer patients with rare HLA phenotypes. CONCLUSIONS: The new ETKAS was able in its first year to meet the goals set at its introduction. In comparison with the old ETKAS, there was a better trade-off between HLA matching and waiting time. The value of computer simulation studies has been demonstrated impressively in the context of organ allocation.

Beneficial effect of HLA-DR matching on the survival of corneal allografts.

BACKGROUND: Although HLA typing and matching have been used for 3 decades, that practice has been poorly implemented in corneal transplantation, mainly because of inconclusive or contradictory analytical results. Consequently, we studied the immune response of corneal transplant recipients to HLA histoincompatibilities in a large homogeneous study. METHODS: All corneal transplantations performed by a single surgeon between 1976 and 1996 were studied. HLA-AB matching was used for recipient selection. All HLA typings were performed by a single experienced laboratory. Population genetic techniques were used to assess the validity of the HLA typings. Mono- and multivariate analyses were performed to identify the factors which significantly influence the survival of corneal allografts. Simulation studies were carried out to demonstrate the effects of mis-typed donor and recipient HLA-DR typings on analytical results. RESULTS: Retransplantation, degree of vascularization, HLA-AB and DR matching, endothelial cell count, graft size, recipient gender, and storage method were identified as significant factors by our monovariate analyses. A Cox proportional hazards survival analysis model identified degree of vascularization and HLA-AB and DR matching as significant prognostic factors when all immunological rejection episodes were used, P=0.000001. When only irreversible immunological rejection episodes were used, panel reactive antibodies, retransplantation, and number of rejection events were also identified, P=0.000001. Simulation studies showed that the effects of HLA-DR matching are abrogated by poor HLA-DR typings. CONCLUSIONS: Corneal allograft recipients have a normal alloimmune response to histoincompatibilities. Demonstration of that fact requires accurate HLA typings.

Permanent detrimental effect of nonimmunological factors on long-term renal graft survival: a parsimonious model of time-dependency.

PURPOSE: We attempted to model and test the pattern of effects of prognostic factors on renal graft survival during the posttransplantation time course. PATIENTS AND METHODS: Patients who received a cadaveric kidney-only transplant between January 1990 and December 1995 in Eurotransplant, who received cyclosporine as induction therapy, and who had a complete follow-up at the time of analysis were included in the study (n= 10614). An index summarizing all covariate information was calculated and used for modeling the time-dependent effects with relation to graft failure. RESULTS: The immunological factors (HLA mismatch and % panel-reactive antibody) were seen to have a slowly decreasing negative effect on renal graft survival. The cold ischemic trauma (>24 hr) exerted a permanent detrimental effect on the grafts. The use of organs obtained from old donors was associated with a constant higher risk of graft loss. CONCLUSIONS: An analysis of determinants of human allograft dysfunction should also study the interaction between the effects and time. Nonimmunological factors had a constant detrimental effect on graft failure, whereas the impact of the immunological factors--although remaining important for late graft loss--very slowly decreased. In the context of marginal transplants, clustering of unfavorable factors should be avoided to prevent late graft losses.

Prognostic indices to predict survival of first and second renal allografts.

In order to predict kidney graft survival, the influence of independent prognostic factors can be examined multivariately and the factors combined into a prognostic index. Data on 7121 patients receiving an unrelated first and 1033 patients receiving an unrelated second transplant from nonliving donors, between 1 January 1984 and 31 December 1987, were analyzed to ascertain the most important prognostic variables up to 4.5 years posttransplantation. Factors found to be significant for graft survival were donor and recipient age and sex, recipient blood group, whether the recipient was diabetic, cold ischemic period, number of HLA-B and - DR mismatches, highest percent panel-reactive antibody, transplant center, and--for second transplants--duration of first graft. A risk score for graft failure, based on the prognostic factors, was developed using these factors and five risk groups (from excellent to very poor prognosis) were identified. This index was tested on an independent data set and showed a good fit when compared with the observed Kaplan-Meier graft survival: patients allocated by the risk score into the "excellent prognosis" group had an observed one-year graft survival of 90.4%, compared with a predicted value of 90.3% for first transplants. Corresponding results for second transplants were 86.2% (observed) and 86.0% (predicted). For the "very poor" prognosis group, the results were 73.4% (observed) and 74.4% (predicted), for first transplants, and 60.9% (observed) and 60.1% (predicted), for second transplants. A prognostic index can therefore identify patients likely to have a high or low graft survival, leading to improved decision-making and aiding the choice of patient management once a recipient has been transplanted.

The interaction between the Lewis blood group system and HLA-matching in renal transplantation.

A retrospective study was initiated to investigate the influence of recipients' Lewis subtype and HLA-matching on cadaveric kidney graft outcome. A total of 1111 patients receiving a first cadaveric kidney graft were analyzed. No difference in one-year graft survival was found between Lewis-negative (73%, n = 133) and Lewis-positive (73%, n = 978) recipients. Further subdivision of the study group into HLA-A,-B well-matched (0 or 1 mismatches [MM]) and poorly matched (2, 3, or 4 MM) revealed a strong deleterious effect of HLA-A,-B mismatching in the Lewis-negative group only. One year graft survival in Lewis-negative HLA-A,-B poorly matched (2, 3, or 4 A,B MM) patients was 60% (n = 67) versus 86% (n = 66) in the Lewis-negative HLA-A,-B well-matched (0 or 1 A,B MM) group (P = 0.004). For the Lewis-positive group the one-year graft survival rates were 72% (2, 3, or 4 A,B MM; n = 498) and 74% (0 or 1 A,B MM; n = 480), respectively (P = n.s.). The additional beneficial effect of HLA-DR matching again turned out to be strongest in the Lewis-negative group. In Lewis-negative, HLA-DR (0 MM) and -A,-B well-matched recipients (n = 36) graft survival was 94% versus only 64% in the Lewis-negative, DR matched, A,-B mismatched (2, 3, or 4 A,B MM) group (n = 25; P = 0.09). In the Lewis-positive, HLA-DR 0 mismatched group the one-year survival rates were 78% (0 or 1 A,B MM; n = 240) and 73% (2, 3, or 4 A,B MM; n = 253), respectively (P = 0.05). Our data suggest that donor recipient selection should not be based on Lewis matching per se. However, since Lewis-negative patients are at high risk of graft failure when receiving HLA mismatched kidneys, they should preferentially receive optimally HLA matched grafts.

Factors contributing to long-term kidney graft survival in Eurotransplant.

We examined the graft survival of 12,883 first unrelated kidney grafts from nonliving donors, transplanted between 1 January 1971 and 31 December 1987 within 52 renal transplantation centers participating in the Eurotransplant organization. The 5-year graft survival increased from 38.8% for the period 1971-1975 to 66.0% for the period 1981-1987 for patients treated with cyclosporine, whereas the half-life increased by only 2 years, from 9.7 years to 11.6 years over the same period, based on grafts functioning at 1 year posttransplantation. Results per HLA locus showed considerable improvements within mismatch groups over the entire period. Large differences between mismatch groups for the early years were observed, but within the cyclosporine era only HLA-B showed a statistically significant difference in half-lives (13.2 versus 9.0 years, for 0 and 2 mismatches respectively, P = 0.013). When other prognostic factors were taken into account, it was revealed by means of an exponential model that number of HLA-B mismatches, donor and recipient age and sex, and recipient diagnosis of diabetes had significant effects on the long-term outcome of the grafts. Depending on the combination of these parameters, estimates of half-life varied from 4.9 to 14.5 years. These results show that matching for HLA-B is still of benefit in the longer term and that other prognostic factors play an important role in predicting the late outcome of renal allografts.

Evidence that the difference in kidney graft survival in DRw6+ and DRw6- recipients may be explained by a blood transfusion policy that is disadvantageous for DRw6+ recipients.

Kidneys transplanted to HLA-DRw6+ recipients have been shown to have an inferior graft survival compared with DRw6- patients. Because pretransplant blood transfusions influence kidney graft survival, we investigated whether the number of blood transfusions contributes to the observed poor graft survival in DRw6+ patients. We have found that the difference in graft survival in DRw6+ and DRw6- recipients may be explained by a blood transfusion policy that is disadvantageous for DRw6+ recipients. Thus, graft survival in DRw6+ recipients was excellent for those who had received only a single transfusion. More transfusions resulted in a gradual decrease in graft survival. When the number of transfusions exceeded 5, graft survival improved again. By contrast, DRw6- recipients showed an improvement in graft survival with an increasing number of transfusions. DRw6+ recipients therefore display inferior graft survival only when they receive 3-5 transfusions. This finding provides a possible explanation as to why the "DRw6 effect" is a controversial issue, and it suggests that DRw6+ recipients should be given a different pre-transplant transfusion protocol than DRw6- patients.

Risk factors for delayed graft function in cadaveric kidney transplantation: a prospective study of renal function and graft survival after preservation with University of Wisconsin solution in multi-organ donors. European Multicenter Study Group.

BACKGROUND: Delayed graft function (DGF) remains an important complication in renal transplantation. In this multicenter study, we investigated the influence of donor and recipient factors on the occurrence of DGF and DGF's effect on long-term graft survival. METHODS: A total of 547 transplanted kidney allografts, retrieved from multi-organ donors, were analyzed, and results were compared with literature on kidney-only donors. RESULTS: Median follow-up of patients without graft failure was 3.4 years. Twenty-four percent of the recipients developed DGF. In univariate analysis, the following factors significantly increased the incidence of DGF: (a) among the donor factors, mean creatinine level >120 micromol/L and prolonged cold ischemia time (CIT); and (b) among the recipient factors, previous transplant(s), no intraoperative use of mannitol, poor quality of reperfusion, absence of intraoperative diuresis, and pretransplant anuria or oliguria. After stepwise logistic regression, donor age, CIT, recipient's number of previous transplants, and intraoperative diuresis proved to be of independent prognostic value for the occurrence of DGF. Overall graft survival was 91%, 87%, and 72% at 3 months, 1 year, and 4 years after transplantation, respectively. In case of DGF, graft survival was approximately 10% lower when compared with cases with immediate graft function (P<0.001). No difference in incidence of DGF was found between grafts of multi-organ donors and kidney-only donors. CONCLUSIONS: DGF results in an approximately 10% higher rate of graft failure. DGF incidence can be reduced by the administration of mannitol during transplantation, which minimizes CIT and optimizes donor management. Grafts from multi-organ donors and kidney-only donors appear to be of equal quality.

Beneficial effect of HLA-A and B matched pretransplant blood transfusions on primary cadaveric kidney graft survival.

The effects of HLA-A and B matched pretransplant blood transfusions on the survival of a primary cadaveric kidney graft were studied prospectively in a group of 15 patients who had never received a transfusion and had never been pregnant. Kidney graft survival at one year was 87%, whereas a group of 14 nontransfused patients who underwent transplantation in the same center (before this study was initiated) had a graft survival of only 7%. Twenty-six patients who received a transplant in the same center just before and after each protocol patient served as controls. There were no prior pregnancies in this group; all patients had received blood transfusions from random blood bank donors. Kidney graft survival at one year was 76% for this control group, which is not statistically different from that found for the protocol group. Graft survival for the 13 contralateral kidneys from the protocol group donors was only 50% at one year. These kidneys, however, were transplanted in various other centers. From our study, prolongation of kidney graft survival could be demonstrated for patients receiving pretransplant HLA-A-and-B-matched blood transfusions. Sera screening indicated that lymphocytotoxicity might be reduced by pretransplant HLA-A-and-B-matched blood transfusions. The presence of pretransplant antibodies with specificities for HLA-A and/or B could be significantly correlated with poor graft survival.

Effect of warm ischemia time and HLA (A and B) matching on renal cadaveric graft survival and rejection episodes.

In a retrospective single-center study the influence of warm ischemia time and simultaneous influence of HLA (A and B) matching on one-year renal graft survival was analyzed in 170 adult recipients of primary cadaveric renal grafts. One-year survival of grafts with warm ischemia times longer than 50 min was only 40% (n = 10). When warm ischemia time was shorter than 50 min, a 1-min increase of warm ischemia time correlated with 1% decrease in one-year graft survival as a result of rejection. This detrimental effect of warm ischemia time on graft survival was not yet significant one month after transplantation, but became more evident as follow-up time was lengthened. Warm ischemia time also correlated with the number of reversible rejection episodes in patients with a graft functioning for longer than one year (P less than 0.04). The beneficial influence of HLA (A and B) matching on one-year graft survival was significant (P less than 0.05 log linear test). This influence was even more evident with longer warm ischemia times. It is concluded that warm ischemia has a detrimental influence on graft survival that is mediated by rejection, and it is suggested that this might be due in part to altered presentation or expression of HLA-antigens of ischemically damaged kidney tissues.

Influence of prophylactic treatment with gamma-immunoglobulins on renal function after kidney transplantation in rhesus monkeys.

The effect of prophylactic i.v. administration of high doses of human gamma-immunoglobulin (IgG) on kidney graft survival was investigated in rhesus monkeys treated with azathioprine and prednisolone. In nontransfused recipients not treated with IgG (controls), graft survival ranged from 9 to 22 days; if nontreated animals had been given three pretransplant blood transfusions, graft survival ranged from 9 to 61 days with 42% of the animals showing a prolonged survival time (greater than 22 days). However, in both transfused and nontransfused recipients, the additional pretransplant administration of IgG appeared to have an adverse effect: about 25% of the animals showed accelerated rejection. In addition, serum creatinine levels in IgG-treated recipients were significantly higher on the 3rd day after transplantation than in non-treated monkeys. We concluded that renal transplant patients should be treated with IgG for protection against life-threatening infections only if they have good kidney function.

The impact of HLA-A matching on long-term survival of renal allografts.

An important contribution of HLA-A antigen matching in renal transplantation was reported initially, hut later publications showed a minor or absent role. We analyzed the contribution of HLA-A locus matching to graft survival in 17,672 first renal transplants from unrelated, nonliving donors. We show that an independent HLA-A matching effect still exists. Due to its relative weakness and late appearance, large numbers and longer follow-up periods are required. The HLA-A matching effect is a significant factor in first renal allograft survival up to 6 years after transplantation, with an increasing effect over time. This is in contrast to the strong, short-lived, effects of HLA-DR and -B matching, which can only be detected up to 6 months and 2 years after transplantation, respectively. A clear additive beneficial effect of HLA-A matching is shown in the group without B and DR mismatches. Therefore, prospective matching for the HLA-A antigens remains important for renal allograft survival.