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A total of 69 individuals received a kidney from a living donor after a TLI-based clonal deletion protocol with no post-transplant maintenance immunosuppression planned. If needed, immunosuppression was started on a patient-specific basis, adding one drug at a time, a strategy we AWN". call "Drugs Added When Needed," or "DAWN. Following this strategy, at last follow-up 40 of the 69 patients (58%) had to be rescued by conventional immunosuppression, 23 (33%) had to be started on daily prednisone and six (9%) remained with no maintenance immunosuppression. The overall rate of de novo donor-specific antibody produced was 36% (in 25 of the 69 patients), and mean time to detection was about four months. The incidence of acute rejection episodes that displayed humoral components was 27% (19 cases), of which 14 were pure antibody-mediated rejection, five combined antibody- and T-cell-mediated rejection, and six were episodes (9%) of pure T-cell-mediated rejection. Finally, this study shows that although complete clonal deletion was not achieved, an important proportion of patients--42%, or 29 of the original 69--could be maintained with prednisone alone or even with no immunosuppression for a total mean follow-up of 13.3 months. Moreover, 16 patients with recent follow-up are surviving with no maintenance immunosuppression or just on prednisone. The mean serum creatinine at last follow-up for these 16 patients is 1.33 +/- 0.2 mg/dL with a mean follow-up of 19.3 months. Clonal deletion can be used to transplant patients without maintenance immunosuppression, adding drugs only as needed.

1. Non-HLA antibodies reactive against CLL and lymphoblast lines were detected by cytotoxicity in sera from 22 patients who had been transplanted with kidneys from HLA identical donors. 2. Whether these antibodies had been responsible for the rejection of the HLA identical grafts remain to be determined. 3. Among 71 patients who received HLA mismatched transplants, and had rejected their grafts, 65 (93%), formed antibodies to HLA or MICA antigens. The 5 patients who did not develop antibodies were shown to have antibodies against CLL and lymphoblast lines, suggesting that these grafts may have been rejected by non-HLA antibodies.

1. The rate of transfusion decreased from 64% in 1992 to 36% in 2000. This need for transfusions continued despite the introduction of erythropoetin. Females were transfused more frequently than males. SLE patients were transfused more often than those with other diseases. 2. Transfusions no longer had a beneficial effect on the outcome of transplantation, but rather with more transfusions, the graft outcome became lower, as might be expected. 3. Rejection of a kidney transplant had the strongest effect on sensitization, followed by transfusion and then pregnancies. Females were more susceptible to sensitization than males. Although non-transfused males should not have been sensitized, as many as 13% were reported to have antibodies. As many as 20% of nulliparous females without transfusions also were reported to have antibodies. 4. SLE patients were most often sensitized among patients with various diseases. Females of all diseases were more sensitized than males. 5. Unsensitized regraft patients had a 3% lower 3-year graft survival than unsensitized first graft patients. Among sensitized patients, regraft patients had a 4% lower graft survival than sensitized first graft patients. 6. Patients with polycystic kidney disease had the highest 3-year graft survival in both the sensitized and non-sensitized patients. Sensitization to a PRA level of less than 50% was not detrimental to patients with all the various diseases. 7. For cadaver donor regraft patients, HLA-DR mismatch had a greater effect than AB mismatch. There was a 10 percentage point lower 3-year graft survival in cadaver donor regraft patients mismatched for 2 DR antigens than mismatched for 0 DR antigens. 8. For living donor transplants, regrafts from 0 AB or 0 DR mismatched transplants had the same graft survival as first transplants.

1. The HLA-matching effect in Type 1 diabetic patients applied only to those receiving a kidney alone. Those receiving simultaneous pancreas transplants did not benefit significantly from HLA-matching, although graft survival was high. Nevertheless, an HLA-matching effect could be shown for grafts from cadaver donors who were 25-35 years of age. Grafts from older donors apparently were more vulnerable to diabetic complications. The highest graft survival in diabetic patients was obtained with HLA-identical living donor grafts-60% at 10 years, which was in marked contrast to the 35% survival rate of HLA-mismatched cadaver donor grafts. 2. Functional graft survival analysis (censoring deaths) of Type 1 diabetics showed that graft survival was low because of deaths, presumably resulting from diabetic complications. 3. The HLA-matching effect was modest for focal glomerulonephritis patients. However, a small HLA-matching effect was noted in retransplants from cadaver donors and grafts from living donors. 4. Patients with polycystic kidney disease had the highest overall graft survival rates in all HLA-mismatch categories. Zero-ABDR-mismatched first cadaver transplants had a 60% ten-year survival rate and a 78% survival rate from HLA-identical living donors. 5. Patient survival in all the disease groups was not affected by HLA matching. Graft failure and return to dialysis apparently did not affect survival of patients. 6. Overall graft survival rates have improved markedly with newer immunosuppressants and improved patient care. The 3-year graft survival rate for the worst mismatches improved from 67% in 1987-90 to 73% for 1990-92 transplants to 73% for 1992-94, 78% for 1994-96, and 80% for transplants performed in 1996-98. 7. Projected 10-year graft survival for patients transplanted since 1994 was 64% for 0-HLA-mismatched grafts and 47% for 5-6 antigen-mismatched transplants--a 17% differential. Thus, despite newer immunosuppression, HLA matching continues to be an important factor.

Grouping US kidney transplant centers according to the number of transplants performed during the past 10 years into those that reported more than 1,000 transplants and all others showed: 1. Ten-year graft survival rates at larger centers were no more than 5% higher than those at other centers. 2. Graft survival rates were most similar between the 2 center groups when the donor was an HLA-identical sibling or when the recipient had chronic glomerulonephritis. 3. Larger centers had a slightly but noticeably higher graft survival rate when the patient had juvenile onset diabetes, when the donor was older than age 60 and when the donor was a spouse. 4. Most differences in graft survival rates between larger and all other centers were apparent only 2-3 years after transplantation, suggesting that the differences reflect long-term management of the patients or that an historical difference existed that has disappeared in recent years.

Impact analysis, showing the proportion of patients in each category, is useful in providing a rapid visualization of the current renal transplant situation. It provides a 2-dimensional view of the number of cases and the success rates of each category. From the graphs, one can readily see the impact of changing policies upon overall results. Efforts to reduce cold ischemia time and increase zero HLA-A, -B, -DR mismatched transplants would have a significant impact. Clearly, the greatest adverse impact factor in cadaver kidney transplants today is donor age: transplants from donors aged 40 and older negatively impact current overall success rates.

Nine years ago, a prospective trial began in all U.S. transplant centers to determine whether the results of renal transplantation would improve with the nationwide shipment of kidneys from cadaveric donors to HLA-matched patients. Since then, the stringency of criteria for HLA matching have been liberalized twice, from sharing only those kidneys that matched at all six HLA-A, -B, -DR antigens, to sharing phenotypically HLA-matched kidneys, and most recently to sharing zero HLA-mismatched kidneys.Data reported to the United Network for Organ Sharing Scientific Renal Transplant Registry from October 1987 to December 1996 were analyzed to examine the transplant results of nationally shared HLA-matched kidneys and the effects of changes to the HLA matching criteria on graft survival and the distribution of HLA-matched kidneys.The overall 1-year graft survival rate of 5102 HLA-matched transplants was 88% compared with 81% for 58,207 recipients of kidneys with at least one HLA mismatch (P0.001). HLA-matched kidneys had a projected 12-year graft half-life, 50% higher than the 8-year half-life of mismatched grafts (P0.01). After the first change in the match criteria in August 1990, 1365 phenotypically matched kidneys with fewer than six HLA antigens identified had an 89% 1-year graft survival rate compared with 84% for 466 six antigen-matched kidneys transplanted before the change. After March 1995, 1067 zero HLA-mismatched kidneys that were not phenotypically identical nor six antigen matched, had a 1-year graft survival rate of 88%. Graft survival has not decreased as a result of these changes in the criteria for national sharing, despite an increase in the percentage of matched transplants from 2.5% during the six antigen-match era to 15.5% during the zero antigen-mismatch era.Changes to the United Network for Organ Sharing policy for national sharing of HLA-matched kidneys have increased the number of patients, and especially minority patients, who can benefit by receiving a well-matched graft without compromising the high graft survival rates provided by an HLA-matched kidney.

The UNOS Scientific Renal Transplant Registry data from October 1987 to December 1996, including information on transplants to 537 patients aged 0-2, 2399 patients aged 3-12 and 5986 patients aged 13-21, were used to examine the results of pediatric transplantation by both univariate and multivariate methods. One-year and long-term graft survival rates were adjusted for 9 covariates including donor source and age, recipient sex, race and disease, and transplant year, HLA mismatches, and transplant center. The adjusted 1- and 5-year graft survival rates were 71% and 60% for ages 0-2, 83% and 64% for ages 3-12 and 85% and 57% for ages 13-21. Except for the youngest recipients, these results compared favorably at 1 year with 86% graft survival among 78,418 adults. The projected graft half-life was highest in patients under age 2 (18 years) and lowest among teenagers (7 years) compared with adults and children (11 years). Univariate analyses revealed a significant 10% graft survival advantage with living donor kidneys for all age groups, but especially for those aged 0-2 in whom survival was 66% with a cadaver donor and 84% with a living donor. The youngest recipients experienced early rejection of the mother's kidney less often than the father's (47% vs 28% in the first 6 months, p0.007). Results in blacks were similar to those in whites during the first year, but the 3.8 year half-life for black teenagers was the lowest among all groups. We conclude that with the exception of very young (age 2 or under) patients, 1-year pediatric renal transplant survival rates are comparable to those in adults, but in the long term, non-compliance and late acute rejection result in an accelerated graft failure rate among teenagers.

An enzyme-linked immunosorbent assay test for measuring and characterizing anti-human leukocyte antigen antibodies in recipient sera received mixed evaluations. Enzyme-linked immunosorbent assay and flow cytometry crossmatch tests using solubulized donor human leukocyte antigens were introduced New methods for allocating kidneys included permissible human leukocyte antigen mismatch, human leukocyte antigen amino acid residue match, and kidney size/human leukocyte antigen match algorithms.

Aside from HLA identical sibling donors, spousal donor transplants are the best living donors because their 3-year graft survival is comparable to that of all other living donors--with the exception of HLA identical siblings. Interestingly, the 14.5 year half-life of spousal donor kidneys was superior to the 10.8 year half-life of other living donor transplants. Better quality kidneys is the principal explanation for higher spousal donor graft survival rates when compared with cadaver donors. This was evident from the 2% anuria rate in the first post-operative day for spouse donor compared with 10% of cadaver donor transplants. Moreover, the requirement for dialysis was 6% for spouse donor grafts compared with 22% of cadaver donor transplants. The damage is not attributable to cold ischemia time but rather to agonal events and shock prior to kidney harvesting. In a survey of 176 spousal renal transplant donors, 175 of 176 said they would advise others to donate a kidney to a spouse--and only one donor advised against it. Of the "yes" responses, 28% provided additional comments enthusiastically recommending it. About 47% reported improvements in the marital relationship, 29% in the sexual relationship, and 25% described improved relations with their children. The fact that the donor reaps many direct personal benefits should make spousal donation the first consideration for living-donation (after the HLA-identical sibling donor).

A new method of residue matching based on three polymorphic upward-oriented amino acid residues on the alpha-helices of the HLA molecule is described. The projected 10-year graft outcome for 1232 transplants with none of these residues mismatched was 47%, essentially the same as for 0 BDR-mismatched kidneys. The projected impact of allocation to recipients in a local pool based on the three residues was a 5% improvement in overall graft survival at 10 years.

The difficulty in achieving long-term survival is demonstrated by the fact that an improvement of 30 percentage points in 1-year cadaver donor survival resulted in only a 10-percentage point improvement over 20 years. In early transplants from 1965 to 1974, the 20-year survival rate of HLA identical siblings was 46%, of parental donors 27%, and of cadaver donors 12%. More recent grafts, performed since 1987, had a projected survival of 57% for identical donors, 30% for parental donors, and 18% for cadaver donors. With respect to HLA matching for cadaver donor kidney transplants, a 0 AB-antigen mismatch produced higher graft survival than did mismatched transplants during the 20-year period from 1965 to 1984. After the introduction of HLA Class II typing in 1980 and general improvements in typing for transplants performed after 1987, the 0 ABDR-mismatched grafts have a projected 20-year survival of 40%. The projected survival rates for transplants with one or more mismatches fall progressively to 13% for transplants that have 6 ABDR mismatches. Thus, the success due to HLA matching has improved ever since the introduction of cyclosporine because of the concurrent improvements in tissue typing for Class I and Class II specificities.

The findings from the UNOS Scientific Renal Transplant Registry are summarized in the following table. We've also provided our opinions on ways to influence the risk factors in the Discussion section. [table: see text]

Primary kidney transplants from living related and cadaveric donors to black recipients failed twice as rapidly as those to white recipients in data reported to the United Network for Organ Sharing Scientific Renal Transplant Registry between 1987 and 1991. The projected half-life for 132 HLA-identical sibling donor transplants in blacks was 15 years versus 29 years for 1,033 whites (P0.001). For recipients of cadaveric grafts, the half-lives were 5 years for blacks (n = 5,282) and 10 years for whites (n = 14,917). The 1-year graft survival rates and half-lives improved with HLA matching in both blacks and whites, but the 2-fold difference in long-term survival rates persisted even among recipients of well-matched grafts. With a zero HLA-A,B-mismatched donor, blacks had an 8-year half-life, compared with 17 years for whites (P0.001). The racial difference was most marked in young adults, with a 15-20% disparity at 3 years between blacks and whites aged 16-30. Pediatric and older black patients had 3-year graft survival rates similar to those of whites. Antilymphocyte globulin or OKT3 prophylaxis improved graft survival by 2% at 1 year and 5% at 2 years among blacks, but the half-life remained 5.6 years. In contrast to these findings in the United States, 63 blacks transplanted in Canada had the same short- and long-term graft survival as whites, suggesting an important long-term influence of the health care system and socioeconomic factors. In addition to improved access to health care and improved HLA typing of blacks, more black donors are needed to provide better matched transplants for blacks awaiting transplants.

In a retrospective study of 84 primary cadaver donor orthotopic liver transplants (OLTs), we investigated the damaging effect of preformed donor-specific antibodies by a standard T-cell warm crossmatch test (TWXM) and a more sensitive flow cytometry crossmatch test (FCXM). The incidence of a positive crossmatch was 12% (10/84) by TWXM and 24% (20/84) by FCXM, respectively. The incidence of 1-month graft failure was 30% (3/10) for patients with a positive TWXM, compared with 23% (17/74) for a negative TWXM. The deleterious effect was more pronounced when the patients were examined by FCXM. Nine of 20 (45%) FCXM-positive recipients lost their grafts within 1 month (p = 0.01) and 8 of those 9 failures occurred within 2 weeks posttransplant. A comparison of graft survival rates at 6 months demonstrated that FCXM-positive patients had a 25% lower survival rate (p = 0.01) than those with a negative FCXM. The positive rate of FCXM was 4 times higher in sensitized patients (PRA 11-100). However, 9 patients in the non-sensitized group (PRA 0-10) had a positive FCXM, and 5 of 9 patients had graft failure within 1 month, suggesting that even a low level of antibodies or non-complement fixing antibodies may have a very damaging effect. This study shows that preformed donor-specific antibodies do have a deleterious effect on allografts. Although the effect is not necessarily expressed as hyperacute rejection, the antibody response is capable of damaging the allografted organs within 1 month. Consideration should be given to crossmatching OLT patients in order to avoid transplantation over a positive crossmatch.

1. We summarize typings of 40 cells for Class I antigens and 20 cultured cell lines for Class II antigens through the International Cell Exchange in 1994. Serologic Class II typings were compared with DNA typings for the same 20 cells. Two hundred eighty-one laboratories participated in the monthly Class I Serum Exchange. One hundred nineteen serology laboratories and 74 DNA laboratories reported Class II specificities on a monthly basis. 2. The average detection levels, as well as the high detection levels, were determined for 16 A-locus and 27 B-locus antigens. Mean detection rates of 95% or greater average detection were obtained for 12 A-locus and 10 B-locus antigens. Lower than 80% agreement was calculated for one A-locus antigen (A74) and 7 B-locus (B46, B48, B61, B67, B73, B75, B77) antigens. 3. We compared discrepancy rates of 10 A-locus and 7 B-locus antigens typed 3 times or more. The false-negative discrepancy rates, i.e. how often the antigen was missed, were greater for more of the B-locus specificities than for the A-locus antigens. B62, having the highest false-positive rate, tended to be overassigned. The discrepancy rates, especially the false-negative rate, for B70 were shown to decrease over a 7-year period. 4. In 1994, 8 laboratories attained records of total no misses for all analyzed antigens. Twelve laboratories had final records of only one discrepancy, and 5 laboratories had impressive perfect records (zero false negatives and false positives) for their yearly antigen reports. 5. Retyping of 12 Class I and 8 Class II reference cells showed improved detection of antigens. Results of a donor typed 4 times over 11 years demonstrated marked improvement, nearly doubling for A33, B38, and B75. Two cells first typed in 1991, then retyped in 1994, showed improved detection for Class II splits by serology and DNA typing. 6. We updated the list of sequenced Class I Exchange cells. Seven new cells were added as well as confirmatory sequence data for A*2403 to the A9.3 (cell 762) and a new B*0705 (cell 715) for previously listed cells. Variants detected in the exchanges for Class I (DT/B7x40, B15, B16, B5x53) and Class II (DRB1*1111, DQB1*02, DR1, DR2) specificities were discussed. Eleven rare or unusual Class II haplotypes were studied in 1994. 7. The mean detection levels were determined for 9 broad DR and 4 DQ specificities by serology and compared to those attained for the respective generic (low resolution) DNA typing.(ABSTRACT TRUNCATED AT 400 WORDS)

1. HLA matching remains a major factor in kidney transplantation. Much of the total graft failures can be eliminated through better HLA matching. 2. Very early effects of HLA matching can be seen with the requirement of dialysis within one week. 3. Even among kidneys which are functioning at the beginning of each period, more frequent rejection treatment with increasing numbers of A,B,DR mismatches was observed. 4. Among functioning kidneys, HLA matching affects the quality of kidney function, as reflected in the serum creatinine levels during all periods. 5. Immunological graft failures (regardless of cause) are strongly associated with HLA mismatching. 6. The effect of HLA matching was similar at centers with high or low overall graft survival rates. 7. The fraction of zero-A,B,DR mismatches has increased dramatically in recent years. However, this is a large difference in the numbers between centers and OPOs. 8. Preformed cytotoxic antibodies to HLA tend to force a higher degree of matching for the A and B loci, resulting from T-lymphocyte crossmatching. 9. Because of the linkage of the 3 HLA loci (A, B, and DR), matching for one often results in matching for 2 or 3 of the loci. 10. Chronic glomerulonephritis patients having DR1 had superior graft survival rates than patients without DR1. 11. HLA frequencies in IDDM, hypertensive nephropathy, CGN and PC were significantly different from controls in many Class II specificities and some Class I specificities.

Cadaver-donor transplants performed before 1987 that had survived for more than 7 years despite having all 6-A,B,DR antigens mismatched were used to develop a list of permissible mismatches. When these permissible mismatches were applied to an entirely different set of cadaver-donor grafts performed after 1987, patients with permissible mismatches had a higher graft survival than those with an equivalent number of immunogenic mismatches. In addition, a new list of permissible mismatches was produced from living-donor transplants which survived for more than one year despite having mismatches. When this list made from living-donor transplants was checked against cadaver-donor transplants, patients with one-permissible-A,B,DR mismatch had a projected 10-year graft survival equivalent to that of zero-A,B,DR mismatched transplants. Patients with one immunogenic mismatch had a significantly lower graft survival. Patients with only permissible mismatches had a higher graft survival than those with immunogenic mismatches and equivalent to patients with one immunogenic mismatch. It was projected that the percentage of patients who can benefit from a zero-A,B,DR mismatched transplant by national sharing can be doubled if one permissible-mismatched grafts are also shared. Even in local pools, the use of permissible-mismatched grafts can be projected to improve 10-year graft survival rates from the current 41% to 52%.

This study was conducted to determine the efficacy of the T cell flow cytometry crossmatch (T-FCXM) test in 841 first cadaver donor transplants. Results showed one-year graft survival rates were 82% for T-FCXM-negative patients, compared with 75% for T-FCXM-positive patients (P = 0.01). Early one-month graft failure was 13 percentage points higher in those with a positive T-FCXM than those with a negative T-FCXM. The positive crossmatch patients also had more frequent immunological failures. A positive T-FCXM was found in 39% of the sensitized patients (PRA > 10%) and 8% of those who had not been sensitized. Patients with a positive T-FCXM in either category had a 74% graft survival rate. Thus, most of the T-FCXM-positive results occurred in patients with complement-fixing antibodies. It is suggested that flow cytometry crossmatching (FCXM) be used prospectively, despite the fact that many patients with a positive crossmatch did have successful transplants (TXs). In the current climate of a cadaver kidney scarcity and large recipient waiting pools, utilization of kidneys for patients with the highest probability of success seems a most prudent policy.

1. Less than 10% of the cadaver kidneys currently allocated have 0-B,DR mismatches. 2. Up to 15% of the kidneys could be regionally allocated using the UNOS algorithm to 0-B,DR-mismatched recipients with a projected 67% 5-year graft survival. 3. Twice the number (32%) of recipients can be identified with zero of 10 A,B residues mismatched with the same 67% 5-year survival. 4. Another doubling (68%) of compatible recipients can be identified with zero of 7 DR supertypic determinants (4 DQ and 3 DRB) and zero of the A,B residues mismatched with a 66% 5-year graft survival. 5. Compressing A,B, and DR antigens to supertypic determinants reduces the racial differences in HLA to the point that 90% of kidneys can be allocated to Black recipients with zero of 3 DRB and zero A,B residues mismatched.

Previous studies of mismatches for a single HLA antigen in kidney transplants have not demonstrated that any single HLA antigen was more immunogenic than another. Here we show that certain mismatched antigens are "permissible" to recipients of certain types and not to others. In this retrospective study of 1,273 living-donor kidney transplants, a mismatch for 27 different, single A,B,DR antigens was evaluated with respect to recipients of various types. Various combinations of donor/recipient incompatibilities were then classified as "permissible" or immunogenic, depending upon the fate of the transplant. This list was then evaluated with 1,905 patients who received cadaver-donor transplants mismatched for a single A,B,DR antigen. Cadaver-donor kidney transplants judged to have received a permissible mismatch in the A, B, or DR loci had graft survival rates equivalent to zero-A,B,DR-mismatched grafts. Among 425 patients with one-A,B,DR-permissible mismatches, one-year graft survival was 89% with a 14.1-year half-life, compared with 966 one-A,B,DR-mismatched grafts with an 89% one-year survival and an 18-year half-life. Based upon these results, we recommend the initiation of one permissible A,B,DR-mismatched transplants for national sharing. This will result in potentially 60% of shared transplants having high long-term graft survival rates.

Trends in one-year graft survival rates seen in the past 30 years were examined in the UCLA and UNOS Registries. Some of the trends noted were as follows: 1. One-year graft survival rates for cadaver-donor transplants improved from 40% to 80% during this 30-year period. One-year patient survival improved from 50% to 95%. Transplants from living-related donors improved in graft survival from 80% to 90-95%. 2. Factors that diminished in importance were: recipient race, sensitization, primary disease, HLA haplotype matching in living donors, recipient and donor sex, kidney sharing, and transfusions. 3. Factors that continue to provide about a 10% variation of one-year graft survival are: cold ischemia time, HLA mismatch, recipient and donor age. 4. Posttransplantation, factors such as first-day diuresis, one-week dialysis, rejection at discharge, and discharge serum creatinine continue to be very important determinants of future outcome in 6 yearly subsets of patients. 5. Induction by ALG and OKT3 was shown in 6 subsets to have no effect on one-year graft survival. 6. Future trend studies will be needed to examine the 5-year long-term effects.

From 1984 to 1990, a 6 to 10% increase in one-year graft survival was noted for patients matched or mismatched for HLA A, B, or DR locus antigens. This improvement was not attributable to matching. In the cyclosporine era, five-year graft survival of 0-ABDR mismatched first cadaver donor transplants was 61% in contrast to 45% survival for the worst 6-antigen mismatched grafts. The long-term half-life of 0-ABDR mismatched grafts was 10.7 years, compared with 6.4 years for the 6-antigen mismatched transplants. The cumulative survival years (a measure of impact) were twice as high for 0-ADR, 0-BDR and 0-AB mismatched grafts compared with 0-ABDR mismatches. On the basis of cumulative survival, five-year survival, and half-life, one might suggest sharing kidneys for 1-2 ABDR mismatch, 1 BDR, 1-2 AB mismatch, and 1-ADR mismatch. Young patients (5 to 25 years old) had lower graft survival rates when receiving poorly mismatched grafts. HLA matching did not influence graft survival in Black recipients, whose half-lives were 3.8 to 4.6 years for all matching categories.

1. The UNOS national sharing program has produced a 5-fold increase in the number of compatible transplants since 1987. 2. Transplants with 0 broad HLA-antigen mismatches had 87% 1-year graft survival and an 18-year half-life, essentially the same result as with conventional matching. 3. Equally impressive results were obtained with public determinant matching: 1-year graft survival ranging from 84 to 88% and a half-life of 12-15 years. 4. Increasing the number of matched determinants improved the results but reduced the number of compatible recipients identified. 5. Less than 10% of the current transplants have 0 public determinants mismatched. This fraction could be increased to 66% with local sharing and to over 90% with national sharing. 6. The results for cadaver transplants would approach those of related kidneys if compatible grafts were transplanted at the 90% rate obtainable with molecular matching.

1. This is a review of 1992 typing of 40 cells for Class I antigens and 18 cultured cell lines for Class II antigens through the International Cell Exchange. Serological typings were compared with DNA typing reports for Class II specificities. Presently, 290 laboratories participate in the monthly Class I exchange. Class II results were received monthly from 166 serology laboratories and from 36 DNA laboratories. 2. In 1992, 11 of the 16 A-locus antigens attained 95% or greater average detection. Nine of the 27 B-locus antigens showed 95% or better mean agreement levels. Antigens such as B46 and B70 continued to show improvement in detection in a 5-year period. 3. We compared discrepancy rates of 7 A-locus and 8 B-locus antigens typed 3 times or more. The rates for the B-locus specificities, especially for percentages of false negatives (ie, how often the antigen assignment was missed), continued to be greater than those for the A-locus antigens. Nevertheless, the discrepancy rates of B35 and B70 decreased dramatically during the last 5 years. 4. We showed the number of laboratories with the total of false negatives and false positives. Nine laboratories achieved perfect records (0 false negatives and false positives) for all analyzed antigens in 1992. 5. Results of retyping of 3 donors over several years were shown to indicate improved antigen detection. 6. Recently recognized HLA-specificities, such as A2403 and B5102, were shown as cell variants studied in previous cell exchanges. Variants of B15, B16, and B40 families were presented, as well as several new A-locus antigens. 7. The low and high rates, in addition to the average detection levels, were indicated for a total of 27 (18 DR and 9 DQ) Class II specificities by serology and by DNA typings. Eight of the 15 DR/DRB1 specificities attained 90% or better average agreement by both serology and DNA. Three of the 9 DQ antigens achieved 90% or better average detection by both methods. 8. Confirmation by DNA typings was demonstrated for 8 Class II specificities with 60% or lower detection levels by serology; the average detection levels by DNA typing was 80% or greater. Confirmation of 2 splits of Class II antigens by DNA typing was shown in 3 cells. 9. The percent detection levels were calculated for 17 DRB1 alleles and 11 DQB1 alleles. Variation in agreement was observed for the Class II alleles. Two DRB1 and 3 DQB1 alleles had average detection levels of 80% or higher.(ABSTRACT TRUNCATED AT 400 WORDS)

The question of whether or not HLA is important in transplantation can now be answered with a definite yes. The nationwide six-antigen-matching program, in which over 100 US transplantation centers have participated, has shown that a high (88% to 90%) 1-year graft survival rate can be achieved when kidneys are shipped to well-matched recipients. Long-term outcome (measured as half-life) is also markedly improved, from an average of 7 years for cadaveric donor transplants to as much as 19 years in the six-antigen-matched recipients. One of the major factors influencing long-term survival is histocompatibility matching, as shown by the survival differences among HLA-identical siblings (25-year half-life), one-haplotype-mismatched parental donors (12-year half-life), and two-haplotype-mismatched cadaveric donors (7-year half-life). For the past 25 years of kidney transplant experience, cadaveric donor half-life has remained stable at 7 years, despite many improvements in immunosuppression protocols. Histocompatibility matching unquestionably offers the best approach to prevention of chronic rejection.

We examined the serological reaction of 50,000 HLA antisera for correlations with amino acid substitutions at 16 variable residues on the A locus and 8 variable residues on the B locus. We identified antisera that produced mutually exclusive allelic reactions corresponding to amino acid variants at the various residues. We assumed that by this procedure, epitopes that were determined by a single amino acid substitution could be identified. Among 55 variable residues on the A locus, antibodies that reacted in an allelic fashion were found for 16, or 32%. These serologically determined epitopes were on the alpha helix for 13 of the 16 residues, and 3 were in the beta sheet. Among 54 variable residues for the B locus, antibodies were found to 8 which reacted in a mutually exclusive pattern. Thus, 13% of the residues were serologically defined. Sixteen "monospecific" HLA specificities were determined by a single residue. Interestingly, many "multispecific" sera could be accounted for by reactions to a single amino-acid defined epitope. We assume that most of the other monospecific and multispecific specificities are determined by conformational epitopes, as described in an accompanying article (Ch. 33).

The subjects of this study were transplant recipients entered in the UCLA Registry file since 1984 and in the UNOS Registry since 1987. [table: see text] 5. Based on the data above, we conclude that the near 20% loss rate in the first year can be roughly allocated as follows: death 3%, technical 3%, agonal kidney damage 6%, and histocompatibility differences 7%. 6. The quality of HLA typing was assessed by examining the frequencies of the various specificities reported for cadaver donors in 8 yearly periods from 1984 to 1991. The A and B loci specificities were remarkably constant. The DR specificities were still undergoing stabilization. 7. No urine output on the first day, which occurred in approximately 10% of the first cadaver-donor transplants, resulted in about a 20 percentage point lower graft survival rate at 1 year. 8. Anuria on the first day increased with cold ischemia time, donor age, cerebral vascular accident donors, and retransplant recipients. 9. Graft survival with anuria on the first day and: [table: see text] 10. When dialysis was required during the first week, there was an approximate 15 percentage point decrease in 1-year graft survival in 25% of the patients. 11. One rejection in the first hospitalization period resulted in 67% 1-year graft survival. More than 1 rejection led to 57% 1-year graft survival. 12. Serum creatinine at discharge was an accurate indicator of subsequent graft survival. Approximately a 7 percentage point drop in 1-year graft survival was noted with each unit of serum creatinine above 2.0 mg/dl.

Based upon data reported to the UNOS Scientific Renal Transplant Registry between October 1987 and November 1991: 1. One-year graft survival rates were 79%, 73% and 62% for recipients of first (20,864), second (3,217), and multiple (673) cadaver donor transplants, respectively. 2. One-year graft survival rates were 94%, 89%, and 90% for first transplant recipients of kidneys from HLA-identical siblings (970), parents (1,487), and 1-haplotype-mismatched siblings (1,206), respectively. 3. Half-lives calculated after the first year were 7 years for cadaver donor transplants, 11 years for parent, 12 years for 1-haplotype sibling and, 27 years for HLA-identical sibling-donor first transplants. 4. The 1-year first transplant survival rate has improved from 78% in 1987-88 to 80% in 1990-91 transplants (p = 0.001). There has been an attendant decline in the percentage of broadly sensitized patients transplanted from 15% in 1987 to 8% in 1990 (p less than 0.01), which may have contributed to rising survival rates. 5. There has been a remarkable improvement in the 1-year graft survival of retransplanted patients from less than 70% in 1987-88 to 78% in 1990 (p less than 0.001). This improvement has been most notable in broadly sensitized patients and those with delayed graft function. 6. Diabetics who received a pancreas and kidney transplant (995) had 81% 1-year graft survival compared to 77% for those who received a kidney transplant only (p less than 0.002). 7. One-year graft survival rates decreased significantly in recipients of kidneys from donors aged under 16 or over 45. Survival was less than 70% when the donor was under 5 or over 60 compared to 81% when the donor was aged 16-45 (p less than 0.001) for recipients of first cadaver transplants. Delayed graft function occurred in 40% of cases when the donor was over 60 and 28% of cases when the donor was under 5. When function was delayed, survival was 50% for these marginal kidneys compared to 68% for younger adult kidneys with delayed function (p less than 0.001). Rejection also had a greater impact on survival of kidneys from donors under 5 or over 60. 8. The 1-year graft survival rate for 2,504 first transplant recipients of cadaver kidneys from young male victims of traffic accidents was 85%. The 1-year graft survival of 2,670 patients given kidneys from older female donors who died of cerebrovascular accidents was 73% (p less than 0.001).(ABSTRACT TRUNCATED AT 400 WORDS)

Some HLA Class I alleles or groups of alleles can be explained by exclusive residues which may explain their structural uniqueness. However, many sera are directed to alleles whose structural uniqueness is explained only by a combination of nonexclusive residues. A program implementing a combinatorial search algorithm was developed to analyze serological data by associating the primary structure of specific alleles to reaction patterns of broad multispecific sera. The method determines the residue or residues whose associated alleles best describe the serum specificity. The raw data reaction patterns direct the search, which utilizes known primary sequence information of HLA Class I alleles. Three-hundred highly positive sera from parous females were analyzed; 74 were highly correlated to the A locus and 125 to the B locus. Some of the remaining sera were associated with multiple loci. Reorganization methods were applied to the data. Clusters of residues associated with certain alleles focus attention on specific locations on the HLA Class I molecule. These regions may be included in, or in close proximity to, the serological determinant. Serological descriptions of certain broad specific sera have been termed "public epitopes." Specificities associated with distinct conserved regions of the Class I molecule offer a molecular basis for many public epitopes. Similar reaction patterns to 3 serologically allelic regions were found in pregnancy allosera, monoclonal antibodies, and transplant recipient sera. The correlated areas were: positions 166 and 167 of the alpha 2 domain alpha helix on the A locus, positions 79-83 of the alpha 1 domain alpha helix on the A locus, and positions 80-83 on the A and B loci.

1. The 1-year graft survival rate for 3,525 Black recipients of first cadaver-donor transplants between 1985 and 1989 was 71%. For 13,866 Whites it was significantly higher at 78%, and 796 Asians had the highest 1-year graft survival rate at 83%. 2. When transplant centers were grouped according to the number of Black patients transplanted between 1985 and 1989, 1-year graft survival rates for Blacks ranged from 67% at centers that transplanted more than 100 Blacks to 74% at centers with 50-100 Blacks to 69% at centers with 1-50 Black transplants. The corresponding survival rates for Whites were 74%, 78%, and 78%, respectively (p less than 0.01 at each center group). 3. When the results were further stratified according to donor race and age, HLA-DR mismatches, and transfusions, a significant 6% difference remained between graft survival rates of Black and White recipients (p less than 0.01). 4. Similar stratified analyses for donor race yielded a significant 8% lower survival rate for Black donor kidneys compared to White donor kidneys (p less than 0.01). 5. More than 25% of Black recipients and donor kidneys were transplanted at 6 of the 204 centers reporting to the UCLA Transplant Registry, whereas 92 centers had transplanted no Black patients. 6. The main difference in survival between Whites and Blacks was among younger patients. There was a 13% difference for those younger than 30 (p less than 0.01), and only a 4% difference among patients older than 45 (p less than 0.05). 7. When HLA-DR antigens were matched, there was no difference in the survival rate between White and Black patients. This result was unaffected by the race of the donor, implying that racial HLA-DR variants may not be a major consideration in matching. 8. Black patients had poor long-term graft survival. The kidney half-life calculated after the first year for Black recipients was 3.7 years, and was 8.7 years for Whites (p less than 0.01). 9. There was a clear "center effect" component to racial differences in first cadaver kidney transplant outcomes related to the size of the Black recipient population. These center effects did not account for the overall difference between Black and White survival rates.

1. A yearly summary of the previous year's cells typed through the International Cell Exchange allows a participating laboratory to compare its own performance with 292 currently participating exchange laboratories, inasmuch as each laboratory receives its individual antigen report. We present an annual summary for the 1990 typings of 40 cells sent for Class I and 20 cells sent for Class II antigens. 2. The mean detection percentages and the detection ranges for 21 WHO-designated (well-defined) and 21 WHO-provisional (with "w" designations, less well-defined) antigens were determined for the Class I cells typed in 1990. Seventeen WHO antigens showed 95% or greater detection levels. The remaining WHO antigens showed at least 90% agreement, with the exception of B38. More variation in detection is observed in the WHO-provisional antigens. Aw33, Bw50, Bw60, and Bw62 showed 90% or greater average detection percents. In recent years, antigens such as Bw46 and Bw70, have shown great improvement in detection. 3. The percent discrepancy rates of 8 HLA-A,B antigens typed 4 times or more in 1990 were presented as well as the total percent discrepancy rates for all Class I antigens. Comparison of 1990 figures with those of 1988 and 1989 shows a marked decrease in the total discrepancy rates. 4. The number of false negatives and false positives for the Class I antigens indicates that few laboratories have trouble typing the WHO antigens; as many as 115 laboratories had 0 misses. However, a greater number of laboratories missed the less well-defined WHO-provisional antigens: 7 laboratories had 0 misses for all the antigens and 4 laboratories had perfect records (0 false negatives and false positives) for cells typed in 1990. 5. In 1990, the cell exchange continued to study new cell variants. An A10 (A26x34) variant was detected in 4 cells and another possible variant, B7x40 (DT), was determined in 3 cells. 6. The average detection percentages and detection ranges were determined for 23 Class II antigens. Improved detection is indicated. At least 9 Class II antigens showed 90% or greater agreement level, of which at least 4 had 95% or greater mean detection. 7. Since the incorporation of DNA typing results in the B-cell line exchange reports in July 1990, the Class II antigen splits in 11 cells have been confirmed or clarified. Two Class II variants were also confirmed by the DNA laboratories. Presently, 145 serology and 7 DNA laboratories are in this exchange.(ABSTRACT TRUNCATED AT 400 WORDS)

1. Two-year 6-antigen-matched graft survival was 82% for first grafts and 72% for second grafts compared to 72% and 60% for the controls. 2. Six-antigen-matched transplants had longer mean ischemia times and recipients had higher levels of antibodies but the effect of these factors was insignificant compared to their effect on the controls. 3. One reason for transplant loss among the 6-antigen-matched recipients was inadequate transplant size. When kidneys from young or old donors were transplanted into heavy recipients, graft survival was 74% compared to 88% for median-age donors. 4. Six-antigen-matched transplants with common phenotypes (greater than 4 cases) had 2-year graft survival of 87% compared to 76% for those which occurred only once. 5. Difficulties in tissue typing certain antigens was shown to have an effect. Six-antigen-matched transplants with antigens defined by at least 80% of the tissue typing laboratories had 89% 1-year graft survival compared to 73% for those with antigens which were more difficult to define. 6. There were fewer homozygous donors and more regraft transplants than expected.

Based upon data reported to the UNOS Scientific Renal Transplant Registry between October 1987 and October 1990: 1. One-year graft survival rates were 78% for 14,203 recipients of first cadaver donor transplants, 70% for 2180 recipients of second cadaver transplants, and 59% for 487 recipients of third or fourth transplants. First transplants from living donors had 90% 1-year graft survival. 2. One-year graft survival was 75% for 2,273 Black recipients of first cadaver transplants and ranged between 79-80% for recipients of other races (p less than 0.001). 3. Broadly sensitized (50% peak PRA) first cadaver transplant recipients had 77% 1-year graft survival versus 79% for nonsensitized or narrowly sensitized recipients. Cadaver retransplant recipients with greater than 10% peak PRA had 65% 1-year graft survival while those transplanted with no antibody had 78% (p less than 0.001). Survival of nonsensitized retransplanted patients was not significantly less than first transplant recipients. 4. Graft survival was 78% at 1 year for both male and female recipients of first cadaver donor transplants. Retransplanted females had significantly higher 1-year graft survival at 70% than males at 67% (p less than 0.01). Male donor kidneys had significantly higher survival rates than female donor kidneys in both first and retransplanted patients. One-year graft survival was 79% and 70% with male donors and 75% and 65% with female donors in first and retransplants, respectively (p less than 0.01). 5. Pediatric recipients (under 16) and older recipients (over 60) of first cadaver transplants had 73% 1-year graft survival compared to 78-79% for those aged 16-60. 6. Among recipients of first cadaver transplants, 1-year graft survival rates varied over a 20% range with the age of the donor. Excluding pediatric and older patients, the best survival rates (81%) were obtained with kidneys from donors aged 16-45. Kidneys from younger and older donors yielded progressively poorer results. The lowest survival was with 181 donors aged 1-5 (60%) and 145 donors over 60 (69%). 7. One-year graft survival was 85% for 274 recipients of 0 HLA-A,B,DR-mismatched first cadaver transplants and 74% for 717 recipients of transplants mismatched for 6 HLA-A,B,DR antigens. Graft survival progressively declined with increasing histoincompatibility. 8. One-year graft survival decreased by 20% if the kidney failed to produce urine in the first hour, from 80-60% in first transplant recipients and from 72-50% in retransplanted patients.(ABSTRACT TRUNCATED AT 400 WORDS)

1. Greater than 50% PRA-sensitized first kidney graft recipients show significantly lower graft survival rates than nonsensitized (0-10% PRA) and moderately sensitized (11-50% PRA) recipients. Most of the effect of sensitization can be seen within the first month posttransplantation. 2. Increases in cellular immunity or antibodies not currently detected by lymphocyte cytotoxicity may account for the decreased graft survival rates in second and multiple graft recipients. One possibility involves the presence of antiplatelet antibodies. 3. Transfusions seem to be the weakest stimulus for sensitization when compared to pregnancy, and to graft failure, which is the strongest. In addition, low numbers of transfusions tend to have a beneficial effect, especially on second kidney graft survival. 4. During the years since the prospective use of the T-cell FCXM by Los Angeles transplant centers, there has been a marked increase in graft survival rates for multiple graft recipients. However, the rates for the sensitized multiple transplant group still remain lower than those for the nonsensitized first and multiple graft groups.

Homozygous DW typing cells were tested for six B-lymphocyte specificities. All four of the second locus specificities of B lymphocytes were strongly associated with the DW specificities. DW1 typing cells were B group 6, DW2 were B4, DW3 were B5, and LD107 were B3. The first B-cell locus antigens 1 and 2 tended to be uniform within the DW groups. From an analysis of the typing responses of a panel of cells to the homozygous typing cells, it has become apparent that the first B-locus specificity present on the homozygous typing cells also plays a role in determining whether a typing response is obtained or not. Thus, the DW3 typing cells were themselves B2 and B5, and cells having B2-B5 were most frequently nonreactive to DW3 in mixed lymphocyte culture. Homozygous typing cells therefore mainly detect the second B-cell locus antigens and, to a lesser degree, the first locus specificities. Stated another way, homozygous typing cells do not define a single specificity, but rather the presence of two B-lymphocyte specificities, even though their responses often reflect matching of only the second B-locus specificity.