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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.
Methods
Primary orthotopic heart transplantations were performed from January 1985 to June 1992 at 104 centers in 24 countries (see the Appendix)14. The participating centers agreed to report all consecutive transplantations at their institutions and to obtain appropriate authorization from patients for participation in the study. A total of 8331 patients were enrolled. All the patients included in this analysis received cyclosporine-based immunosuppression, usually in combination with steroids and azathioprine. In addition, 63 percent of the recipients received prophylaxis against rejection with polyclonal or monoclonal antilymphocyte antibodies during the immediate post-transplantation period. HLA typing was performed at the tissue-typing laboratories of the participating centers. The transplantation procedures were reported to the study center at the University of Heidelberg shortly after transplantation, and clinical follow-up data were requested every three months during the first year and yearly thereafter. We also recorded the maintenance doses of immunosuppressive drugs that the patients were receiving one year after transplantation. The associations of outcome with HLA matching and maintenance immunosuppression were compared with those obtained in a parallel multicenter study on renal transplantation13,14. No patients were excluded. Actuarial rates of graft survival were computed according to the method of Kaplan and Meier15. The log-rank test, weighted regression,16 and Cox proportional-hazards regression17 were used for statistical evaluation. In the Cox model, the transplantation procedures were given a score of 0 if no mismatch or one HLA-A, B, or DR mismatch was involved, a score of 1 if two mismatches were involved, and a score of 2 if three to six mismatches were involved.
Results
Compatibility for the HLA-A, B, and DR loci was significantly associated with the outcome of heart transplantation (Figure 1). The mean (±SE) rate of graft survival at three years among the 128 patients with no mismatches or only one mismatch was 83 ±4 percent, as compared with a rate of 76 ±2 percent among the 439 patients with two mismatches and 71 ±1 percent among the 7764 patients with three to six mismatches (P<0.001). For the purposes of this analysis, we combined the groups of patients with no mismatches and one mismatch because their numbers were relatively small and the rates of graft survival were similar (three-year survival, 80 ±7 percent for the 47 grafts with no mismatches and 84 ±6 percent for the 81 grafts with one mismatch; P>0.1). The survival rate of grafts with no mismatches or only one mismatch was consistently high in different geographic regions at three years: 84 percent in North America (n = 75), 81 percent in Europe (n = 41), and 82 percent on other continents (n = 12).
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When the association of graft survival was considered separately in terms of the compatibility of each of the HLA loci (HLA-A, B, and DR), the results were less impressive than those obtained when the analysis included all three loci. Transplants with zero, one, two, three, or four HLA-A or B mismatches had three-year survival rates of 77 ±5 percent, 73 ±3 percent, 71 ±1 percent, 72 ±1 percent, and 71 ±1 percent, respectively (P = 0.57), and the corresponding rates for transplants with zero, one, or two HLA-DR mismatches were 75 ±2 percent, 72 ±1 percent, and 71 ±1 percent (P = 0.04).
To exclude the possibility that the observed effect of HLA matching resulted from a skewed distribution of other influential factors, the results of the univariate analysis were subjected to Cox regression analysis. The transplants were classified into three categories according to the number of HLA-A, B, and DR mismatches (zero to one, two, or three to six) and analyzed in the context of factors selected on the basis of their apparent influence in univariate analyses of the data. The factors analyzed, the cutoff points chosen for the analysis, and the distribution of factors among the three categories are shown in Table 1. The analysis established an independent, statistically significant influence of HLA compatibility on graft survival (P = 0.005) (Table 1). The regression coefficient for the three categories of mismatches was 0.235, corresponding to a relative risk of 1.26. Thus, transplants with two HLA-A, B, or DR mismatches had an approximately 25 percent greater likelihood of failing within three years of transplantation than transplants with no mismatches or only one mismatch, and the likelihood of failure was an additional 25 percent higher when there were more than two mismatches.
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The results of this study provide evidence of a significant influence of the extent of HLA matching on heart-transplant survival. With the collaboration of transplantation centers around the world, it has been possible to obtain information on 128 grafts that were well matched for the HLA-A, B, and DR antigens. These transplants, which had no mismatches or only one mismatch, constituted 1.5 percent of all those reported to the collaborative study, indicating that grafts were not allocated according to HLA compatibility; this rate would be expected from a random allocation of donor organs4. That well-matched transplants had a significantly better survival rate than poorly matched ones is an important finding, since it establishes that HLA compatibility influences the success rate of heart transplantation as well as of kidney transplantation.
Well-matched heart transplants had a particular survival advantage during the first six months after transplantation, suggesting that poorly matched grafts are subject to a higher rate of acute immunologic rejection. This conjecture is supported by the results of detailed investigations in single-center studies8,9,10,11,12. The current data do not allow us to conclude that HLA matching improves the rate of long-term rejection of heart transplants to a degree similar to that for kidney transplants18; larger numbers of well-matched transplants will have to be studied with prolonged follow-up.
During the course of the collaborative study, clinicians at the participating centers frequently commented that they considered the study an academic exercise, since the time constraints surrounding donor-heart preservation made prospective HLA matching impossible. We would argue instead that the results of the current study are not merely of academic interest. Because of the complexity of the HLA system, however, one would have to resort to a multicenter system of organ sharing, similar to that used with donor kidneys, in order to optimize HLA matching for heart-transplant recipients. The susceptibility of donor hearts to ischemic damage remains the chief limiting factor. Kidneys can be preserved up to 36 hours,18 but our data indicate that the survival rate of heart transplants is significantly reduced with preservation times of more than 4 hours. Nevertheless, this constraint does not preclude the possibility of organ sharing even within relatively large geographic areas.
To minimize the preservation time, HLA typing of recipients and donors could easily be performed before the removal of donor organs. Combining the waiting lists of centers from neighboring geographic regions would improve the likelihood of achieving good HLA matches. We have obtained evidence that the sharing of donor hearts while remaining within the four-hour preservation limit would be feasible if regional pools of approximately 1000 patients needing transplantation were formed. By adjusting a recently described computer-allocation model for cadaveric kidneys4 to include realistic conditions for heart transplantation (allocation of 20 percent of donor hearts on an emergency basis to patients without consideration of HLA matching and limitation of the mean waiting time to seven months), we found that it would be possible to perform transplantations in 32 percent of patients with no HLA-A, B, or DR mismatches or only one mismatch and in another 31 percent with only two mismatches. On the basis of the survival data shown in Figure 1, this would result in a 5 percent higher overall rate of transplant survival at three years.
Pools of 1000 patients could be formed within an air-transport radius of approximately two hours both in Western Europe and in some regions of North America, allowing transplantation of well-matched hearts within the four-hour preservation limit. For example, the heart-transplant waiting list for the geographic area served by the Eurotransplant organization (encompassing Germany, the Netherlands, Belgium, Luxembourg, and Austria) currently includes more than 900 patients19. Of 739 transplantations performed within this region in 1992, 521 (71 percent) involved hearts procured from distant donor centers. An air-travel time of two hours and a cold-ischemia time of four hours are the generally accepted limits of feasibility for the use of hearts obtained at centers other than the one performing the procedure. Thus, we are not proposing novel guidelines for the procurement of donor hearts but only for their allocation. Except for patients requiring urgent transplantation, it would seem feasible to allocate hearts on the basis of HLA matching. In the future, the introduction of improved techniques of heart preservation allowing longer periods of ischemia may further simplify the sharing of donor hearts.
The results of the analysis of HLA compatibility in heart transplantation are at variance with those obtained in a parallel collaborative study of cadaveric kidney transplantation,13 in that we found no further decline in the survival rate of organs as the number of HLA mismatches increased from three to six. This led to speculation that the higher doses of immunosuppressive drugs administered to heart-transplant recipients, as compared with those given to kidney-transplant recipients, might be responsible for this effect. That heart-transplant recipients tend to receive higher doses of cyclosporine and azathioprine as a precautionary measure is understandable, since graft rejection in such patients is usually fatal, whereas kidney-transplant recipients who undergo rejection can return to dialysis. It is conceivable that the more intensive immunosuppressive treatment of heart-transplant patients erases any difference in the survival rates of grafts with three, four, five, or six mismatches. Although this might be thought of as an argument in favor of more intensive immunosuppression in all transplant recipients, including those receiving kidneys, it is important to point out that the higher rate of malignant lymphomas reported in heart-transplant patients after transplantation is also believed to be the result of more intensive immunosuppressive treatment20. Our data indicate that the rate of graft survival in heart transplantation could be increased by transplanting organs with better HLA matches; in theory, at least, the resulting reduced requirement for immunosuppression should lead to a reduced rate of malignant conditions after transplantation.
We are indebted to the staff members at the 104 participating transplantation centers for their support of this collaborative project and to IBM Scientific Center, Heidelberg, Germany, for computer hardware and software support.
Source Information
From the Department of Transplantation Immunology, Institute of Immunology, University of Heidelberg, Heidelberg, Germany. Supported in part by grants from Deutsche Stiftung Organtransplantation and Deutsche Krebshilfe.
Address reprint requests to Dr. Opelz at the Institute of Immunology, University of Heidelberg, Im Neuenheimer Feld 305, D-69120 Heidelberg, Germany.
References
The data for this analysis were provided by transplantation centers in the following cities: Aalst, Belgium; Ann Arbor, Mich.; Auckland, New Zealand; Baltimore; Belo Horizonte, Brazil; Bergamo, Italy; Birmingham, Ala.; Bologna, Italy; Boston; Cape Town, South Africa; Charleston, S.C.; Charlotte, N.C.; Chicago; Columbus, Ohio; Dallas; Detroit; Edmonton, Alta., Canada; Essen, Germany; Falls Church, Va.; Fort Wayne, Ind.; Geneva; Gothenburg, Sweden; Graz, Austria; Halifax, N.S., Canada; Hamburg, Germany; Hannover, Germany; Hartford, Conn.; Heidelberg, Germany; Helsinki, Finland; Hershey, Pa.; Indianapolis; Innsbruck, Austria; Iowa City, Iowa; Jerusalem, Israel; Kaiserslautern, Germany; Kansas City, Mo.; Lausanne, Switzerland; Leuven, Belgium; Liege, Belgium; Loma Linda, Calif.; London, Ont., Canada; Louisville, Ky.; Madison, Wis.; Manchester, United Kingdom; Maywood, Ill.; Medellin, Colombia; Melbourne, Australia; Miami; Milan, Italy; Milwaukee; Montreal; Moscow, Russia; Nancy, France; Nantes, France; Nashville; New Haven, Conn.; New Orleans; New York; Newcastle upon Tyne, United Kingdom; Oklahoma City; Oslo, Norway; Ottawa, Ont., Canada; Padua, Italy; Pamplona, Spain; Papworth-Cambridge, United Kingdom; Paris; Pavia, Italy; Philadelphia; Pittsburgh; Portland, Oreg.; Prague, Czech Republic; Quebec City, Quebec, Canada; Rennes, France; Richmond, Va.; Rochester, N.Y.; Rome; Salt Lake City; San Diego, Calif.; San Francisco; Seattle; St. Louis; Strasbourg, France; Sydney, Australia; Toledo, Ohio; Toronto; Tucson, Ariz.; Turin, Italy; Udine, Italy; Vancouver, B.C., Canada; Washington, D.C.; Wichita, Kans.; Zagreb, Croatia; and Zurich, Switzerland.
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Related Letters:
HLA Compatibility and Graft Survival after Heart Transplantation
Hauptman P. J., Vereerstraeten P., Abramowicz D., Andrien M., Opelz G., Wujciak T.
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Full Text
N Engl J Med 1994;
331:404-405, Aug 11, 1994.
Correspondence
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