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In corneal transplants the risks of acute rejection and graft failure decrease with increasing recipient age, but kidney graft survival analyses tend to show the opposite effect. Why is this? Cadaveric kidney transplants performed in the UK and Republic of Ireland between 1985 and 1993 (UKTSSA database) were analysed by multifactorial methods to identify major factors affecting graft survival. In a study database that had been censured for technical failure and death with a functioning transplant, it was shown that increasing recipient age was associated with decreasing risk of graft failure at 1 year. This is consistent with the view that kidney transplants, like corneal transplants, are less likely to be acutely rejected as the age of the recipient increases.

The accumulation of highly sensitized patients (HSP) on renal transplant waiting lists is a problem faced by all transplant registries. We have studied the HLA class I serological reactivity of 20 random HSP and have related antibody specificity to primary amino acid sequence. In six patients we identified significant correlations (chi 2 test, r > or = 0.93) between panel reactivity and specific amino acid substitutions characteristic of HLA-A, -B, and -C public epitopes. Antibody reactivity was associated with up to three public epitopes in each patient. The 12 separate antibody specificities identified were associated with 10 residues. Seven correlated with HLA-A locus substitutions (Glu-62/Gly-65, Lys-66, Arg-114, His-114/Tyr-116/Lys-127, Thr-142/His-145 [x2], and Thr-149), two with HLA-B locus substitutions (Thr-24, Ser-24) and three with interlocus antibodies associated with either HLA-A and B (Leu-82/Arg-83 [x2]) or with HLA-B and -C substitutions (Leu-163). This information allowed us to predict HLA class I allelic products of known primary sequence that would react negatively with each HSP serum. Windows of acceptable mismatches (WAMMs) can thus be delineated with a view to crossmatch negative transplantation without the need for exhaustive serological analysis. Surprisingly we found that WAMMs for these patients included up to 80% of the 10 commonest HLA class I haplotypes in the British population with four patients being crossmatch compatible with A1,3; B7,8. These observations lead us to propose a more intelligent approach to transplanting HSP based on epitope analysis and definition of WAMMs.

Forty percent of kidney transplants function for more than 10 years, allowing their recipients a lifestyle that is dialysis-free. Causes of success or failure of transplants are grouped into patient-related immunogenetic, pre- and perioperative, and postoperative factors. Some factors turn out to be interdependent, eg, the effect of pretransplantation transfusion and ethnic mismatch or donor age and ischemia; thus, no single analysis can be considered definitive. However, in documenting recent evidence gleaned predominantly from multifactorial analysis, we hope to assess relative risks associated with clinically important factors more accurately.

We show how to estimate expected waiting time to transplantation and match grade potential for each patient awaiting kidney transplantation on a multicenter waiting list. We predict that some easily well-matched patients may be unlikely to receive a well-matched graft through accepting an earlier offer of a poorly matched kidney. Other patients, who are difficult to match, may be unlikely to receive even a poorly matched kidney within a reasonable time.

Highly sensitized patients tend to accumulate on renal transplant waiting lists. A long period of time is often needed for the identification of a compatible graft possessing the rare HLA antigens against which these patients are not immunized. The aim of this study was to identify factors which could explain the fact that the percentage of highly sensitized patients on the Swiss waiting list is one of the highest in Europe. Although no definite conclusion is possible, it seems that this phenomenon is not related to the fact that many of these patients have received mismatched grafts. It seems rather to result from the relatively high rate of transplantations for non-sensitized versus highly sensitized patients in comparison to what is encountered in other countries. The fact that this probably represents only a relative increase in hypersensitized patients is confirmed by the stability of the absolute number of these patients on the waiting list during recent years.

Many studies have shown long-term benefits of HLA matching in kidney transplantation. By examining rates of graft loss within consecutive posttransplant intervals, using data from the UK Transplant Service, we show that the long-term benefits of HLA matching are due to reduction of the graft failure rate within five months of transplantation. After 5-months, HLA-A,B,DR matching appears to have little impact on graft loss. We suggest that graft losses after 5 months may be attributable to non-HLA targets.

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.

A total of 3653 first cadaver kidney transplants in nondiabetic recipients over 15 years of age, performed in 30 transplant centers throughout the United Kingdom between 1978 and 1983, were analyzed to discover which of many recorded recipient, donor, surgical, and tissue-matching variables were important for graft survival, and in which postoperative period they exerted their maximum influence. A considerable effort was invested in checking the validity of the data and the appropriateness of the statistical methods. The duration of dialysis prior to transplantation was associated with a substantially reduced risk of graft failure, particularly at later postoperative times. Good HLA-B locus matching was also found to enhance graft survival--but, by contrast, HLA-A locus matching showed no significant effect on survival. Recipient age over 45 years, high serum reactivity, and grafts with anoxia time (the interval between circulatory arrest and perfusion with ice) exceeding 10 min were found to be associated with poor graft survival. Trends in survival were identified across calendar years of transplant, such that early graft failure (0-15 days) had increased in recent years, whereas later graft failure (greater than 15 days) had declined.

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.

The purpose of this study was to perform a rigorous statistical analysis of the benefits of HLA-A,B and DR matching in renal transplantation. Graft survival in 2282 first cadaver kidney transplants, recorded and followed up by the United Kingdom Transplant Service (UKTS), was analyzed using the piecewise proportional hazards regression method. The results show that substantial improvements in graft survival are obtained when there is DR compatibility and at most one A or B mismatch, but that there is little advantage in tissue matching unless this degree of matching can be attained. So far, few graft recipients have benefited substantially through tissue matching (24% of kidneys exchanged through UKTS in 1984). This is partly attributable to unresolved technical problems in DR typing. However simulations show that under ideal conditions, with a pool of 3000 patients awaiting transplantation, considerable improvements in graft survival can be obtained in over 60% of recipients.

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.

An analysis of pooled data from transplants performed between 1977 and 1981 in 29 centers throughout the United Kingdom and Ireland revealed that the pattern of loss varied according to cause and postoperative time. Loss from rejection was characterized by a bimodal pattern in which early (0-25 days) and late (26-100 days) peaks of rejection were distinguishable. Rejected second transplants exhibited this phenomenon more than first transplants, and the loss was proportionately greater during the early period, suggesting that prior sensitization played an important role. Graft loss from technical causes and recipient death showed distinctly different patterns of loss. These findings suggested that, when possible, transplant survival statistics should be analyzed separately according to postoperative time and cause of loss. In applying these preliminary observations of the pooled data to a comparative study of the results in the different centers it was noted that such comparisons could be substantially affected by random variability in estimates of actuarial survival rates. Therefore, a simple method of ranking was developed in which centers were allocated to high or low survivorship categories, or to an indeterminate category when the standard error in estimated actuarial survival was relatively large. Whereas the variation in loss rate from death with a functioning transplant (DWFT) was found to be indistinguishable from random variability, both nonimmunological failure (NIF) and immunological failure (IF) of the graft were found to be legitimate bases for ranking. Furthermore, center ranking based on IF at 0-25 days failed to exhibit a significant relationship with IF at 26-100 days, which could indicate important center differences associated with antirejection treatments during these two periods. These results showed that, ideally, time-cause parameters should be analyzed separately when comparing transplant survival statistics in different centers.

The matchability of a patient awaiting kidney transplantation is his propensity for being 'well-matched'. We present two methods for estimating matchability. It is commonly supposed that phenotype frequency is a good predictor of matchability. We show a correlation of only 0.3 between matchability and phenotype frequency using the definition of 'well-matched' used by the UK Transplant Service. We also show that ABO type and HLA homozygocity can affect matchability.