Evaluation of HLA matching for CREG antigens in Europe.

BACKGROUND: In North America, cross-reactive antigen group (CREG) matching was introduced recently for cadaver kidney allocation. This is expected to result in improved graft outcome and an increased number of transplants for patients with rare HLA antigens. METHODS: We analyzed the impact of CREG matching using the data of the Collaborative Transplant Study for 59,516 first cadaver transplants performed in Western Europe. The 10 HLA class I CREGs described by Takemoto et al. were used for a comparison with the conventional HLA-A+B mismatching scheme. RESULTS: Transplant outcome depends primarily on the number of HLA-A+B mismatches and not on the CREG match grades. In a retrospective analysis, CREG mismatches correlated with the number of HLA-A+B mismatches. However, in computer simulations, we found that prospective CREG matching is not associated with beneficial HLA-A+B matching. CONCLUSION: The positive CREG matching effect observed in retrospective analyses is caused by the underlying effects of conventional HLA-A+B matching. CREG-oriented cadaver kidney allocation in Europe would, therefore, be inferior to the current conventional HLA-A+B+DR allocation.

HLA compatibility and organ transplant survival. Collaborative Transplant Study.

The influence of HLA compatibility on organ transplant survival was analyzed in more than 150,000 recipients transplanted from 1987 to 1997 at transplant centers participating in the Collaborative Transplant Study. A statistically highly significant effect of HLA matching on graft and patient survival rates was found in the analysis of kidney transplants (P < 0.0001). Ten years after transplantation, the graft survival rate of first cadaver kidney transplants with a complete mismatch (6 HLA-A+B+DR mismatches) was 17% lower than that of grafts with no mismatch. During the first post-transplant year, the class II HLA-DR locus had a stronger impact than the class I HLA-A and HLA-B loci. During subsequent years, however, the influence on graft survival of the three loci was found to be equivalent and additive. For optimal graft outcome, compatibility at all three HLA loci is, therefore, desirable. The excellent correlation of HLA matching observed in recipients of cadaver kidneys with very short ischemic preservation (0-6 hours) or recipients of kidneys from living unrelated donors contradicts reports that short ischemia can eliminate the influence of matching. Although HLA has a significant effect on graft outcome regardless of the state of presensitization, the matching effect is potentiated in patients with highly reactive preformed lymphocytotoxic antibodies. Among first cadaver transplant recipients with an antibody reactivity against > 50% of the test panel, the difference in graft survival at 5 years between patients with 0 or 6 mismatches reached 30%. A collaborative project, in which molecular DNA typing methods were employed, showed that the correction of serological HLA typing errors by more accurate DNA typing results in a significantly improved HLA matching effect. Moreover, matching for the class II locus HLA-DP, a locus that can be typed reliably only by DNA methods, showed a significant effect in cadaver kidney retransplants, especially in the presence of preformed lymphocytotoxic antibodies. The analysis of heart transplants showed a highly significant impact of HLA compatibility on graft outcome (P < 0.0001). This result is of particular interest because donor hearts are not allocated according to the HLA match. A biasing influence of donor organ allocation (i.e. a preferential allocation of good matches to good risk recipients) can, therefore, be excluded. In liver transplantation, neither matching for HLA class I nor HLA class II could be shown to influence transplant outcome.

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.

Association of chronic kidney graft failure with recipient blood pressure. Collaborative Transplant Study.

Immunological rejection is the most important cause of kidney transplant failure. Recently, nonimmunological causes of long-term allograft failure have become more widely appreciated. In primary chronic renal disease, blood pressure is of overriding importance for long-term renal function. The role of blood pressure in determining long-term transplant outcome has not yet been established. We studied the influence of blood pressure post-transplantation on long-term kidney graft outcome in 29,751 patients. Outpatient blood pressure measurements were recorded and reported to the Collaborative Transplant Study. Graft and patient survival rates were analyzed over seven years in relation to blood pressure. Increased levels of systolic and diastolic blood pressure post-transplantation were associated with a graded increase of subsequent graft failure (P < 0.0001). Chronic graft failure was significantly associated with blood pressure even when patient death was censored (P < 0.0001). Cox regression analysis established increased blood pressure as an independent risk factor for graft failure. We conclude that post-transplant blood pressure is a highly significant predictor of long-term kidney graft outcome. Whether aggressive lowering of blood pressure improves long-term transplant outcome will have to be studied prospectively.

Prospective evaluation of pretransplant blood transfusions in cadaver kidney recipients.

BACKGROUND: A beneficial effect of pretransplant transfusions on graft survival was demonstrated in the early 1970s. In the mid-1980s, however, retrospective studies showed that transfusions had lost their graft-protective effect in the cyclosporine era. During the last 10 years, deliberate transfusion pretreatment of transplant patients has been discontinued. METHODS: Within a collaborative project of 14 transplant centers, prospective recipients of cadaver kidney grafts were randomized to receive either three pretransplant transfusions or transplants without transfusions. RESULTS; The graft survival rate was significantly higher in the 205 transfusion recipients than in the 218 patients who did not receive transfusions (at 1 year: 90+/-2% vs. 82+/-3%, P=0.020; at 5 years: 79+/-3% vs. 70+/-4%, P=0.025). Cox regression analysis showed that this effect was independent of age, gender, underlying disease, prophylaxis with antilymphocyte antibodies, and preformed lymphocytotoxins. CONCLUSIONS; Transfusion pretreatment improves the outcome of cadaver kidney transplants even with the use of modern immunosuppressive regimens.

Evaluation of the permissible mismatch concept.

Maruya et al. described a method of separating one HLA-A+B+DR mismatched transplants into permissible and immunogenic categories (published in Clinical Transplants 1993). For the permissible subgroup, they observed an outcome similar to that of zero-A+B+DR mismatched transplants. The classification was based on the HLA type combination of donor and recipient. We evaluated this concept with the data of the Collaborative Transplant Study (CTS). We did not obtain significant differences between the outcome of immunogenic and permissible mismatched transplants. The pairwise p-values for the comparison of zero-mismatched with permissible mismatched transplants are significant for cadaver transplants. The indifferent results obtained in our analysis do not support the concept of permissible mismatches. A more restrictive definition of the permissible mismatches might be helpful. The current method appears to be of insufficient reliability due to the relatively small numbers of transplants in the individual subgroups used to identify permissible combinations.

[Effect of HLA compatibility on kidney transplantation]. / Einfluss der HLA-Kompatibilität auf die Nierentransplantation.

The influence of the HLA system on the success rate of kidney transplantations was evaluated in a worldwide collaborative study. The results confirm the influence of the HLA chromosome on transplants from related donors. Moreover, a highly significant effect of compatibility for the HLA-A, -B, -DR antigens was observed in cadaver transplants (p < 0.0001). The great importance of a good quality of tissue typing was emphasized by a) the observation that a significant influence of compatibility for the HLA-A, -B antigens was evident only if donors and recipients were typed for 'split' specificities and not when they were typed for 'broad' antigens, and b) an improved effect of HLA-DR compatibility when serological typing errors were corrected by molecular (DNA) typing. Computations show that kidney allocation according to the best possible HLA compatibility results in a gain of 800 transplant function years per 1,000 transplantations over a 10-year period.

The influence of HLA compatibility on graft survival after heart transplantation. The Collaborative Transplant Study.

BACKGROUND: In cardiac transplantation, it is standard practice for donor hearts to be allocated to recipients without consideration of the extent of HLA matching. Because the HLA system is highly polymorphic, the likelihood that donor hearts will be well matched to their recipients by chance alone is extremely small. It has therefore not been possible in the past to analyze adequately the success rate of transplantation with HLA-matched hearts. METHODS: We initiated a collaborative study in 1985 to evaluate the influence of HLA compatibility on graft survival in heart transplantation. Data were collected from 104 centers in 24 countries. RESULTS: Of the 8331 patients, 128 received a graft with no HLA-A, B, or DR mismatches or only one mismatch. This frequency (1.5 percent) corresponds to the rate that would be expected from a random allocation of donor organs. The three-year rate of graft survival correlated strongly with HLA compatibility, decreasing from a mean (+/- SE) of 83 +/- 4 percent for the 128 donor hearts with no mismatches or only one mismatch to 76 +/- 2 percent for the 439 hearts with two mismatches and 71 +/- 1 percent for the 7764 hearts with three to six mismatches (P < 0.001). Multifactorial Cox regression analysis showed that this effect was independent of the age and sex of the donor and recipient, the type of underlying disease, the duration of cold ischemia, and the use of prophylaxis with antilymphocyte antibodies (P = 0.005). CONCLUSIONS: Graft survival in heart transplantation is significantly influenced by the extent of HLA compatibility.

A proposal for improved cadaver kidney allocation.

The allocation of cadaver kidneys for transplantation should have two objectives: a fair distribution of kidneys among the waiting recipients and a high success rate. Currently, organ exchange organizations are following mainly a policy of success oriented allocation in that the kidneys are distributed according to the best achievable HLA match. A consequence of this policy is that patients with rare HLA phenotypes experience prolonged waiting times and that there are large kidney exchange imbalances among transplant centers. Based on theoretical considerations, we described previously the selection routine COMB which was aimed at decreasing excessive waiting times. In this study we present an extension of this routine called XCOMB which builds on realistic conditions according to the current Euro-transplant waiting list. This new procedure decreases the average and maximum waiting time, adjusts for rare HLA phenotypes and HLA homozygosity, provides for a reasonably balanced kidney exchange rate among centers, and guarantees an HLA match distribution and overall transplant success rate near the theoretically possible optimum. The program was tested in an extensive simulation based on actual data derived from 35,000 cadaver kidney transplants. Although more complex than procedures currently in use, the program's efficient software allows the selection of a patient within one second from a waiting list of 10,000 potential recipients, using readily available computer hardware.

Computer analysis of cadaver kidney allocation procedures.

Data of 32,000 donors were utilized for a computer simulation to analyze the effect of selection parameters on the outcome of kidney transplants. If the HLA match grade is considered for organ allocation, the overall 1-year graft survival rate is up to 7% higher for first cadaver transplants and up to 12% higher for second transplants than if HLA matching is disregarded. This solely success-oriented organ allocation method, however, leads to prolonged waiting times for patients with rare HLA phenotypes. We developed a selection procedure that yields results near the theoretical optimum: 95% of all patients can be transplanted with 0-2 HLA-A, -B, -DR antigen mismatches, the average waiting time decreases to 20 months, and no patient needs to wait longer for a transplant than 6 years. The overall graft survival rate is only 0.4% lower than the rate obtainable with strictly HLA-oriented allocation. The method prevents "poorly matchable" patients from accumulating on the waiting list. Additionally, the unfavorable race ratio in the North American recipient pool can be largely normalized.