Weighing Optimal Graft Survival through HLA Matching against the Equitable Distribution of Kidney Allografts
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《新英格兰医药杂志》
At almost exactly the same time that Dr. David Willard, whose letter to the editor appears in this issue of the Journal (page 624), received three skin grafts in order to help select the best kidney donor for a patient with end-stage renal failure, I was also the recipient of three skin grafts. My grafts, however, were placed in an attempt to establish whether or not what would later be called "the" HLA antigens were actually the transplantation antigens. Thanks to the help of dozens of other volunteers, these experiments established that HLA antigens are indeed the major human histocompatibility antigens.
The next step was for patients who had survived the transplantation procedure and their kidney donors (parents or siblings) to be HLA typed. The hypothesis was that if HLA matching really mattered, we should find an excess of HLA-identical donor–recipient pairs. This was indeed the case for both sibling-to-sibling and parent-to-child transplantations. Similar findings were reported by Rose Payne, Jean Dausset, Paul Terasaki, and others.
On the basis of these findings, a proposal to start the first international organ-sharing organization was advanced in 1967. Its name was Eurotransplant. The initiative was enthusiastically received, and in a remarkably short time, kidneys were allocated according to the best HLA match between patient and donor in the Netherlands, Belgium, Luxembourg, Germany, and soon other countries. Additional organ-sharing organizations were started in France, the United Kingdom, Scandinavia, and the United States; the U.S. organization is called the United Network for Organ Sharing.
There were good reasons why Eurotransplant and other organ-sharing organizations were so welcome: the hope that HLA matching would have a major beneficial effect on kidney and patient survival, which at the time were often dismal; the shortage of organ-transplantation facilities (most transplantation centers could perform no more than one transplantation at a time, and Eurotransplant helped to locate not only a suitable recipient, but also a transplantation center); and the responsibility taken by Eurotransplant in helping physicians make decisions about which patient was to receive a transplant and which one had to wait.
Initially, matching and donor allocation were based on nine cross-reacting HLA antigens, including HLA Bw4 and HLA Bw6. It worked (see Table), thus proving that even partial matching for HLA can improve graft survival. The honeymoon between the HLA serologists and clinicians did not last very long, however. Almost from the beginning there was friction, because surgeons who were in charge of patients who needed a transplant had to explant a kidney and ship it to another transplantation center. In addition, although it had been shown repeatedly that HLA matching improves graft survival, many mismatched grafts survived and functioned well for many years. Those in the field began to speak of the "relative importance" of HLA in organ allocation, implying that it had to be weighed against time on the waiting list, clinical urgency, and other relevant factors. On one important point, however, there was still agreement: the crossmatch between donor and recipient should be negative.
Table. The Influence of HLA Match Grade on Graft Survival and the Frequency of Chronic Rejection.
After several decades of strife between clinicians, who were faced with the inequity of organ allocation to white and nonwhite patients, and organ-sharing organizations, which were primarily concerned about optimizing the graft's chances of survival — an essential consideration, in view of the shortage of allografts — it was agreed that "fully matched" kidneys had to be shared among centers, while the matching criteria for the remaining transplants could be less stringent. The question then became one of defining the term "fully matched." Despite convincing evidence that the more precise (high-resolution) and complete the typing, the better the graft survival, there was general agreement that high-resolution typing would be counterproductive, because it would exclude too many patients with rare HLA types from transplantation. Therefore, kidneys were allocated on the basis of a median-resolution match for HLA-A, HLA-B, and HLA-DR or HLA-B and HLA-DR only.
It was soon realized that even matching for only the B and DR loci puts nonwhite patients at a disadvantage. In this issue of the Journal, Roberts et al. (pages 545–551) address this problem. In a simulation study, they show that matching for HLA-DR only would improve equity in the distribution of organs between whites and nonwhites, while diminishing graft survival by only 2 percent during the first three years after transplantation.
The study by Roberts et al. is an important step toward the formulation of a just and scientific system of distributing kidney allografts. It also confronts us with the challenge of discovering why some mismatched grafts survive whereas other similarly mismatched kidneys fail. Studies of the differential immunogenicity of HLA-antigen mismatches, the effects of non-HLA polymorphisms, and the influence of exposure to maternal alloantigens during fetal life or to alloantigens in blood transfusions might be enlightening and might facilitate the design of protocols for attaining immunologic tolerance.
It is essential to view the study of Roberts et al. — as important as it is — as an interim report because of its follow-up of no more than three years. Patients who have received a transplant should be included in lifelong follow-up studies if we want to learn the long-term effects of matching for only the DR locus on graft and patient survival, the risk of cancer, and the possibility of weaning patients from immunosuppressive therapy and attaining true tolerance. Although over the past decades, the 10-year rate of overall survival has increased from about 30 percent to 50 percent, a few allografts transplanted from haploidentical or unrelated donors in the 1960s, long before HLA matching was introduced, are still functioning today. It is our task to make this option available to all our patients.
Source Information
From the Europdonor Foundation, Leiden, the Netherlands.
Related Letters:
Changing the Priority for HLA Matching in Kidney Transplantation
Thorsby E., Pfeffer P. F., Spital A., Wendt K. J., Kamoun M., Sellers M. T., Roberts J. P., Wolfe R. A., Port F. K.(Jon J. van Rood, M.D., Ph)
The next step was for patients who had survived the transplantation procedure and their kidney donors (parents or siblings) to be HLA typed. The hypothesis was that if HLA matching really mattered, we should find an excess of HLA-identical donor–recipient pairs. This was indeed the case for both sibling-to-sibling and parent-to-child transplantations. Similar findings were reported by Rose Payne, Jean Dausset, Paul Terasaki, and others.
On the basis of these findings, a proposal to start the first international organ-sharing organization was advanced in 1967. Its name was Eurotransplant. The initiative was enthusiastically received, and in a remarkably short time, kidneys were allocated according to the best HLA match between patient and donor in the Netherlands, Belgium, Luxembourg, Germany, and soon other countries. Additional organ-sharing organizations were started in France, the United Kingdom, Scandinavia, and the United States; the U.S. organization is called the United Network for Organ Sharing.
There were good reasons why Eurotransplant and other organ-sharing organizations were so welcome: the hope that HLA matching would have a major beneficial effect on kidney and patient survival, which at the time were often dismal; the shortage of organ-transplantation facilities (most transplantation centers could perform no more than one transplantation at a time, and Eurotransplant helped to locate not only a suitable recipient, but also a transplantation center); and the responsibility taken by Eurotransplant in helping physicians make decisions about which patient was to receive a transplant and which one had to wait.
Initially, matching and donor allocation were based on nine cross-reacting HLA antigens, including HLA Bw4 and HLA Bw6. It worked (see Table), thus proving that even partial matching for HLA can improve graft survival. The honeymoon between the HLA serologists and clinicians did not last very long, however. Almost from the beginning there was friction, because surgeons who were in charge of patients who needed a transplant had to explant a kidney and ship it to another transplantation center. In addition, although it had been shown repeatedly that HLA matching improves graft survival, many mismatched grafts survived and functioned well for many years. Those in the field began to speak of the "relative importance" of HLA in organ allocation, implying that it had to be weighed against time on the waiting list, clinical urgency, and other relevant factors. On one important point, however, there was still agreement: the crossmatch between donor and recipient should be negative.
Table. The Influence of HLA Match Grade on Graft Survival and the Frequency of Chronic Rejection.
After several decades of strife between clinicians, who were faced with the inequity of organ allocation to white and nonwhite patients, and organ-sharing organizations, which were primarily concerned about optimizing the graft's chances of survival — an essential consideration, in view of the shortage of allografts — it was agreed that "fully matched" kidneys had to be shared among centers, while the matching criteria for the remaining transplants could be less stringent. The question then became one of defining the term "fully matched." Despite convincing evidence that the more precise (high-resolution) and complete the typing, the better the graft survival, there was general agreement that high-resolution typing would be counterproductive, because it would exclude too many patients with rare HLA types from transplantation. Therefore, kidneys were allocated on the basis of a median-resolution match for HLA-A, HLA-B, and HLA-DR or HLA-B and HLA-DR only.
It was soon realized that even matching for only the B and DR loci puts nonwhite patients at a disadvantage. In this issue of the Journal, Roberts et al. (pages 545–551) address this problem. In a simulation study, they show that matching for HLA-DR only would improve equity in the distribution of organs between whites and nonwhites, while diminishing graft survival by only 2 percent during the first three years after transplantation.
The study by Roberts et al. is an important step toward the formulation of a just and scientific system of distributing kidney allografts. It also confronts us with the challenge of discovering why some mismatched grafts survive whereas other similarly mismatched kidneys fail. Studies of the differential immunogenicity of HLA-antigen mismatches, the effects of non-HLA polymorphisms, and the influence of exposure to maternal alloantigens during fetal life or to alloantigens in blood transfusions might be enlightening and might facilitate the design of protocols for attaining immunologic tolerance.
It is essential to view the study of Roberts et al. — as important as it is — as an interim report because of its follow-up of no more than three years. Patients who have received a transplant should be included in lifelong follow-up studies if we want to learn the long-term effects of matching for only the DR locus on graft and patient survival, the risk of cancer, and the possibility of weaning patients from immunosuppressive therapy and attaining true tolerance. Although over the past decades, the 10-year rate of overall survival has increased from about 30 percent to 50 percent, a few allografts transplanted from haploidentical or unrelated donors in the 1960s, long before HLA matching was introduced, are still functioning today. It is our task to make this option available to all our patients.
Source Information
From the Europdonor Foundation, Leiden, the Netherlands.
Related Letters:
Changing the Priority for HLA Matching in Kidney Transplantation
Thorsby E., Pfeffer P. F., Spital A., Wendt K. J., Kamoun M., Sellers M. T., Roberts J. P., Wolfe R. A., Port F. K.(Jon J. van Rood, M.D., Ph)