Search

1. Clinical corneal transplantation has been performed for over a century, but many elements leading to a successful outcome have yet to be identified. 2. Because there are limitless supplies of tissue, the supply of corneas need never fall short of demand. Nevertheless, retrieval rates vary widely among regions in the UK due to uneven organization of services. 3. Organ culture of corneas improves the quality of transplanted tissues because it allows time for substandard material to be discarded. The outcome appears to equal other storage methods. 4. Between 1987 and 1991, 4,560 corneal transplants were performed by 428 surgeons at 216 centers in the UK and were registered with CTFS. Of these, 3,213 were evaluable for graft survival, rejection, and other measures of visual outcome. 5. Unifactorial analysis revealed that the percentage of graft survival at one year was 89% and rejection-free survival was 87%. However, the hazard of rejection appeared to increase at or after the time of suture removal. 6. The percentage of recipients in whom CVA was 6/24 or better (able to read normal text with correction) improved from 16% preoperatively to 59% at 3 and 70% at 12 months postoperatively overall. In patients transplanted purely for visual reasons, improvement was 78% and 83% at 3 and 12 months, respectively. 7. Interim results of multifactorial analysis suggest that the risk of graft failure, rejection, and decreased CVA increased in association with the following factors: surgeons who reported fewer than 50 transplants to the study; recipients under 10 years of age; previously failed grafts (the more failed grafts, the greater the risk); grafting for nonvisual reasons; certain diagnoses; and vascularization of the corneal bed prior to transplantation. 8. Astigmatism was investigated in 880 cases at 3 months postoperatively. Preliminary analysis indicated that the risk of severe astigmatism was influenced by suturing technique and large differences between (> 0.25 mm) donor and recipient trephine size. 9. The effects of HLA matching were evaluated in 542 transplants. HLA-A and B matching reduced the risk of rejection during the first 450 days posttransplant, but HLA-DR matching appeared to increase the risk of rejection. 10. A rat model designed to simulate clinical corneal grafting was used to investigate the interaction between immunosuppression and matching. Whereas MHC mismatching could be overcome with topical dexamethasone, non-MHC mismatching appeared resistant.(ABSTRACT TRUNCATED AT 400 WORDS)

1. The International Marrow Unrelated Search and Transplant (IMUST) Study 1 provides novel prognostic data on outcome of unrelated-donor (UD) searches for patients with well-defined clinical characteristics. Case-types analyzed by multifactorial methods reveal the importance of HLA phenotype, ethnic mismatching, and stage of disease at search request, in predicting search outcome. White patients, with common HLA types and early disease, were least likely to suffer search failure. In contrast, searches for non-White patients with unusual HLA phenotypes and advanced disease were most likely to fail. Of importance, 70% of patients had HLA phenotypes defined as uncommon. 2. Overall donor yield at the 2 UK registries between 1989 and 1991 was 7%, significantly below expectations. Reasons for this shortfall are that theoretical predictions did not consider ethnic mismatch and logistical delays incurred by outdated UD search routines and most importantly HLA-typing inaccuracies. 3. IMUST Study 2 is a prospective multicenter-controlled cohort study comparing HLA-identical sibling donor (ID) and UD-bone marrow transplantation (BMT) for factors affecting BMT outcome. Generous support was provided by 83 BMT centers worldwide. An interim analysis of 165 UD- and 368 ID-BMT, with at least 6 months follow-up after BMT, is described. Unifactorial analysis showed a probability of engraftment at day 100 of 89% after UD- compared with 98% after ID-BMT (p < 0.001). Probability of Grades II-IV acute graft-versus-host disease (AGvHD) at 100 days was 52% after UD- compared with 42% after ID-BMT (p < 0.01). Probability of overall survival at day 400 was 42% after UD- compared with 63% after ID-BMT (p < 0.001). Survival on day 400 of those patients receiving UD-BMT for early disease was encouraging at 52%. 4. Multifactorial analysis was performed on combined data from UD- and ID-BMT cohorts to identify various factors predicting engraftment, AGvHD, and overall survival. Survival after UD-BMT was increased by center experience of UD-BMT and the use of additional pretransplant immunosuppression. Survival was decreased in UD- compared with ID-BMT, by female donor to male recipient and poor-risk disease. Engraftment was improved in ID- compared with UD-BMT, and after UD-BMT at centers experienced in UD-BMT. Engraftment worsened with the use of ex-vivo T-cell depletion for GvHD prophylaxis, in chronic myeloid leukemia, and in male recipients of female marrow.(ABSTRACT TRUNCATED AT 400 WORDS)

1. One-year graft survival of 218 patients transplanted through the SOS Scheme for highly sensitized recipients was 65%. There was significant improvement in the graft survival of 135 patients transplanted from 1986 to 1988, compared to the 83 patients transplanted from 1984 to 1985 (70% vs 56% at 1 year). 2. Of the 513 patients entered into the SOS Scheme, 218 (42%) received a graft, and of those 218, 179 were transplanted within 1 year. 3. Sex and previous graft history influenced the patient's sensitization status. Males with previously failed grafts and females waiting for their first transplant appeared at greater risk of becoming highly sensitized. 4. HLA matching improved graft survival in highly sensitized patients. The effect of matching was most evident for DR and for HLA-B and DR combined. The effect of matching for HLA-A was minimal. 5. HLA-DR1-positive individuals appeared to be at lower risk of becoming highly sensitized. In addition, DR1-positive highly sensitized patients had superior graft survival compared to DR1 negative recipients.

In this chapter the linear model for the relationship between cumulative HLA mismatches and graft loss is shown to be invalid. HLA-A and -B mismatches and HLA-DR mismatches appear to differ in potency. A single mismatch at the HLA-DR locus is associated with a maximum risk of graft loss. These findings permit a simple division of transplants into beneficially matched (000, 100, and 010) and nonbeneficially matched (all other 23 combinations). In centers where more than two-thirds of patients were treated with CsA at three months, a similar dichotomy between beneficially and nonbeneficially matched transplants was observed, confirming the view that CsA-treated patients benefit from good HLA-A,B and DR matching. Organ-sharing schemes are designed to realize the full potential of matching and their potential can be investigated by simulation studies. These indicate that if all organs were unconditionally offered to a multicenter pool of more than 3,000 recipients, more than 60% of transplants could be beneficially matched.

1. New initiatives are required to investigate late allograft failure and its causes. 2. In the UK from 1978 to 1988 major reductions in graft loss rates occurred during the posttransplant epoch from 16-365 days but beyond 1-year failure rates show no overall changes. 3. Cyclosporine has its greatest impact during the interval from 16-365 days posttransplant and there is no evidence from these data of its impact in reducing graft losses beyond 1 year, but switching to other drugs was not taken into account. 4. The relative risk of graft loss associated with beneficial HLA matching apparently dwindles and is negligible beyond 1 year. 5. Major risk factors affecting late kidney allograft failure have yet to be modeled and evaluated.

1. The risks associated with nonbeneficial matching constitute a persistent hazard to the transplant over a long period. 2. The benefits of HLA matching and CsA are separate and additive. 3. There is no evidence that beneficial matching is not relevant to all (UK) centers. 4. Contemporary typing methods are expected to improve the accuracy of typing and reduce kidney cold-ischemia times. 5. Organ sharing increases the numbers of beneficial matches. 6. Patients with easily matchable ABO-HLA phenotypes should wait for beneficially matched transplants. 7. Patients with phenotypes that are difficult to match should be intelligently mismatched after due consideration of responder status, acceptable mismatches, and cross-reactive groups. 8. Organ sharing does not prejudice graft survival. 9. Wastage is minimized with a central clearing house. 10. Organ sharing reduces the incidence of high sensitization. 11. Organ sharing is cost effective. For these reasons we repudiate the view that organ sharing is now superfluous.

Our next quinquennial plan for transplantation studies extends MPI to corneal and unrelated marrow transplantation. It applies Bayesian hierarchical modelling to regional variation in donor procurement and continues a program of special studies to augment national databases with respect to kidney, corneal, heart and liver transplantation. It promotes research collaboration among European and other organ exchange organizations as pioneered in the Council of Europe 1986 Study on High Sensitization, which showed the effectiveness of the network of European organ exchange organizations in liaising with transplant units.