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This chapter provides the nomenclature for factors of the HLA system, 2002. A number of previously described class I and II gene fragments within the HLA region are named in this system. Official designations are given to these gene fragments. The names LMP2 and LMP7 used previously for the two proteasome genes in the HLA class II region have been renamed by the Human Genome Nomenclature committee (HGNC) as PSMB9 and PSMB8, respectively. This system introduces the additional digit for synonymous variation and all allele names that are currently five digits or above are renamed accordingly. The use of an optional “N’” or “L” suffix to an allele name to indicate either “Null” or “Low” expression was introduced in previous Nomenclature Reports. Three new suffixes are introduced in this system. An “S” to denote an allele specifying a protein that is expressed as a soluble “Secreted” molecule but is not present on the cell surface; a “C” to indicate an allele product that is present in the “Cytoplasm” but not at the cell surface; an “A” to indicate “Aberrant” expression where there is some doubt as to whether a protein is expressed or not. There is evidence of differential splicing of HLA-G that leads to the production of both membrane-bound and soluble forms of the same allele. The IMGT/HLA Sequence Database contains sequences for all HLA alleles officially recognized by the WHO Nomenclature Committee for Factors of the HLA System and, provides users with online tools and facilities for their retrieval and analysis.

Should HLA antigens that were mismatched in a renal transplant that failed be avoided in subsequent transplants? There were 890 retransplantations reported to the UCLA International Kidney Transplant Registry between 1985 and 1993 that had been performed in the face of a repeat HLA incompatibility. The 1- and 3-year regraft survival rates were 67% and 55%, respectively, for these retransplants, compared with 73% and 60% for 3220 regrafts with no HLA-A, -B, or -DR antigens mismatched twice (P = 0.030). When the repeat HLA-mismatched antigens were examined by locus, there was no difference in regraft survival comparing patients with no repeat HLA incompatibilities with those mismatched twice for HLA-A or -B antigens only, but there was a significant long-term decrease in survival of patients mismatched twice for HLA-DR antigens. The 377 patients mismatched twice only for HLA-A or -B antigens had 1- and 3-year regraft survival rates of 67% and 59%, respectively, compared with 65% (P = 0.289) and 50% (P = 0.025) for 281 patients with HLA-DR repeat mismatches only. Repeat mismatches for a combination of HLA-A or -B and -DR antigens resulted in 65% and 44% 1- and 3-year regraft survival in 129 patients. The half-lives for retransplants with repeat HLA class I, II, and I and II incompatibilities were 8, 6, and 4 years, respectively (P = 0.005). The data do not support preemptive avoidance of repeat HLA-A or -B incompatibilities. The crossmatch test excludes relevant mismatches. Repeated HLA-DR incompatibilities are not excluded by crossmatch tests and have a deleterious effect on long-term regraft survival. HLA-DR antigens mismatched in a previous failed transplant should be avoided.

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.

The success of cadaveric renal transplants in the first year is determined largely by events that transpire during the transplant hospitalization. This conclusion is based upon analyses of data on 19,525 cadaver donor renal transplants performed since October 1987 and reported to the UNOS Scientific

1. A total of 61 patients were treated with a clonal deletion protocol and transplanted without planned post-transplant immunosuppression. 2. Twenty-nine (48%) patients did not develop any donor-specific anti-HLA antibodies after the transplant, with a median follow-up of 158 days and a mean sCr of 2.1 mg/dL at the last follow-up. 3. Only 23% of the patients who received a DST of 60 mL produced DSA after the transplant, while 68% of the patients who received a bigger DST dose did. 4. Small doses of donor-specific transfusions (60 mL) elicited smaller specific responses, allowing efficient deletion of the reacting clones, creating conditions in which donor-specific anti-HLA antibodies were not produced. 5. A better deleting agent is needed to achieve higher rates of success using the clonal deletion protocol.

We show the ability of bortezomib to remove donor-specific HLA antibody from kidney allograft patients, the drug acting as a proteasome inhibitor, providing targeted therapy against antibody-producing plasma cells. Ten out of thirteen patients (77%) experienced primary DSA reversal, and in the remaining three patients the MFI of their primary DSA was dramatically reduced. Bortezomib is a viable therapy to treat donor-specific HLA antibody in allograft recipients. The potential for long-term benefits--and complications--are still unknown. Prospective trials are being conducted at the University of Cincinnati, Cincinnati, OH; at the Mayo Clinic, Rochester, MN; and at IKDRC-ITS, Ahmedabad, India.

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.

Since diarrhoea and weight loss are so characteristic of acquired immune deficiency syndrome (AIDS), it is per- haps ::,urprising that only recently has there been careful investigation of the gastrointestinal tract of affected patienLs. Human immunodeficiency virus (HIV) infection of human intesti- nal mononuclear cells (C. Fiocchi, Cleveland) and of intestinal epi- thelium (M.F. Kagnoff, San Diego) have been demonstrated and it is clear that the changes in the intestinal epithelium are subtly differ- ent from those of other infectious and inflammatory diseases of the gut (M. Zeitz0 Berlin; A.G. Cummins, Adela!de). This report has concentrated al- most entirely on the gastrointestinal tract since that is mv ,~wn interest, but paoers relevant to other mucosal surfaces including the eye, the nose, the genital tract, the urinary tract and respiratory system were abundant; two interesting papers demonstrated possible effects of cigarette smoking on mucosal immunology (G.F. Cope, Leeds; J.R. Barton, Edinburgh). J. Holmgren and A.M. Svennerhoim (Gothenburg) separately presented details of progress in the develop- ment and application oral vac- cines; the oral cholera vaccine containing cholera B sub-unit cross- reacts immunologically with E. coil heat labile enterotoxin (LT) and has been shown to afford significant pro- tection against diarrhoea caused by LT producing enterotoxigenic E. coil (ETEC) in humans. Anne Ferguson is at the Department of Medi- cine, Western General Hospital, Edinbu~h EH4 2XU, UK. The WHO Nomenclature Committee for Factors of the HLA System t met during the Seventh Intematin. nal Congress of Im- munology to consider additions to pre- vious reports. Here new data on DNA sequences of alleles and of three new loci are presented and names of new a/le!~s and led defined by nucleotide or inferred amino acid sequences are given.

1. Although the number of cadaver donor transplants did not increase substantially over the past 10 years, unrelated living donor grafts increased from 153 in 1991 to 1,661 through 2000. Use of spousal and other unrelated donor organs contributed to this increase. There was a modest increase in living-related donor transplants from 2,328 in 1991 to 3,451 in 2000. 2. Cadaver donor graft survival at one year improved from 84% in 1991 to 90% in 2000. In contrast, one-year graft survival of living donor transplants only improved from 93% in 1991 to 95% in 2000. 3. Throughout the 10-year period, approximately 13% of transplants were repeat transplants from cadaver donors and roughly 8% were regrafts from live donors. 4. Cadaver donor transplants into White recipients declined from 68% in 1991 to 60% in 2000. For living donors, the percentage of White patients remained constant at about 70%. 5. Graft survival in patients of all races was about equal at one year but diverged at 3 years, with Asians having the highest and Blacks having the lowest 3-year graft survival rates. 6. Average donor age increased from 31.7 in 1991 to 36 in 2000 for cadaveric donor transplants and 37.9 in 1991 to 40.4 in 2000 for living donor transplants. Cadaveric kidneys from donors older than 50 years of age yielded significantly lower 3-year graft survival. 7. Average recipient age for cadaveric donor transplants increased from 42.1 in 1991 to 46.8 in 2000. The average recipient age for living donor transplants also increased steadily from 33.7 in 1991 to 42.9 in 2000. There was relatively little effect on graft survival rates for advanced age recipients. 8. The percentage of sensitized recipients receiving cadaver donor grafts declined from 27% in 1991 to 21% in 2000. Similarly, sensitized recipients receiving living donor grafts decreased from 17% in 1991 to 13% in 2000. Graft survival in patients with more than 50% PRA was lower at 3 years for patients receiving cadaveric donor grafts. Highly sensitized patients receiving living donor grafts had graft survival rates similar to those who were not sensitized. 9. Cold ischemia times decreased from an average of 24.2 hours in 1991 to 18.9 hours in 2000. Improved graft survival rates over those 10 years were noted in all groups, and even cold ischemia times more than 36 hours yielded 3-year graft survivals comparable to those with lower cold ischemia times in 1998. 10. The need for dialysis has remained constant at about 23% over the last 10 years for patients receiving kidneys from cadaveric donors. The rate of dialysis for patients receiving kidneys from living donors was about 5% for each of the 10 years examined. First day anuria increased from 11% in 1991 to 16% in 2000 for cadaver donor transplants and 3% in 1999 to 5% in 2000 for living donor grafts. 11. Cadaveric donor patients requiring dialysis had a 3-year graft survival rate of 63% if there was no first day anuria and 56% if they had first day anuria. This is in contrast to 80% 3-year graft survival for those with immediate diuresis and no need for dialysis. The 3-year graft survival rate for those receiving living donor grafts and needing dialysis was 58% if they had first day diuresis and 41% if they ware anuric on the first day. Conversely, those who had first day function and did not require dialysis had 89% 3-year graft survival. 12. Among the patients receiving cadaveric grafts with first day diuresis there was a marked reduction in those with rejection, from 21% in 1991 to 5% in 2000. Similarly, for this type of patient receiving living donor grafts, the reduction was 17% in 1991 to 5% in 2000. However, graft survival among these patients did not change significantly. The greatest improvement was noted in those with first day anuria and no rejection. 13. Patients who did not require dialysis, and had rejection prior to discharge decreased markedly from 17% in 1991 to 3% in 2000 in those receiving cadaveric grafts and 15% in 1991 to 3.9% in 2000 for those receiving living donors. Graft survival of cadaveric transplants in those needing dialysis, with and without rejection, improved the most in the 10 year period. 14. Hospitalization days for cadaveric transplant recipients were reduced from 19 days in 1991 to 10 days in 2000 and 16 days in 1991 to 8 days in 2000 for recipients of living donor grafts. There was an increase in discharge serum creatinine values from 2.3 mg/dl in 1991 to 3.3 mg/dl in 2000 for cadaver donor grafts. 15. Double therapy was utilized for about 15% of cadaveric and living donors. There was a sharp increase in induction therapy, peaking at 51% in 1994 and decreasing to 5% by 2000 for cadaveric donor transplants. Induction did not improve graft survival for either cadaver or living donor transplant recipients. 16. Triple therapy improved graft survival of White and Black patients, but did not affect the half-lives in either race. 17. The lower graft survival from older donors was not affected by triple therapy for cadaver donor transplants. Triple therapy removed the donor age effect for recipients of living donor grafts. 18. Triple therapy practically eliminated the effect of sensitization for cadaveric donor grafts. Both double and triple therapy virtually eliminated the sensitization effect for living donors. 19. Triple therapy significantly improved the survival of kidneys with more than 36 hours cold ischemia time so that 3-year graft survival was 76% at 3 years compared with 81% for kidneys stored 1-12 hours. 20. Triple therapy improved the 3-year graft survival of kidneys with first day anuria from 50% for double therapy to 69% for triple therapy in cadaver donor transplants. For living donor transplants, there was a similar improvement from 57% with double therapy to 72% with triple therapy. 21. Triple therapy improved the 3-year cadaveric graft survival rate of kidneys requiring dialysis from 51% with double therapy to 67% for triple therapy. There was a similar improvement for living donors needing dialysis from 37% to 61% at 3 years.

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.

We have defined the new allele HLA-B*4012, which had been isolated from a black individual. It was initially recognized as a serologically unique allele when typing her father for renal transplantation. The HLA class I phenotype was A*0201,*6602; B*4001,*4012; Bw6; Cw*0304,*1505. Sequencing from exon 1 through intron 3 of B*4012 was performed. B*4012 is identical to B*4001 and B*4010 in exon 3, and in the 3' part of exon 2, but it is unique in that exon 1 and the 5' part of exon 2 are identical to B*1503, B*1509, B*1510, B*1518, B*1523, and B*1529. The generation of this allele is best explained by a recombination event in exon 2 (break point between nucleotides 205 and 222 from the beginning of the coding region) of B*4001 or B*4010 with one of these B*15 variants as a donor allele. Its unique serological feature (B48, B60, B70, and B72 reactivity) is consistent with the sequence data of its donor alleles.

We have cited more than 23 studies showing that de novo development of anti-HLA antibodies is associated with increased acute and chronic rejection and decreased graft survival in kidney, heart, lung, liver, and corneal transplants. Antibodies to both HLA class I and class II antigens seem to be detrimental. Antibodies of the IgG isotype and possibly the IgM isotype were clinically relevant. Most studies showed that donor-specific antibodies were associated with rejection and graft loss. Therefore, HLA antibodies provide a clinical readout for patient alloreactivity that may have the ability to distinguish graft dysfunction due to immunologic and nonimmunologic causes. Antibody may act as a critical trigger for rejection of allografts and may serve as an early indicator of a slowly smoldering chronic rejection that is not manifested at a given time by biochemical measures such as serum creatinine levels. The effectiveness of various drugs on chronic rejection should be evaluable by their effects on HLA antibody production. We predict that recently developed ELISA and flow cytometry techniques using purified HLA antigen will increase the clinical relevance of posttransplantation HLA antibody monitoring by (1) allowing the detection of low levels of donor antibody; (2) easily distinguishing the isotype and target (HLA class I or class II) of the antibodies; and (3) correlating the antibody with specific graft pathology.

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.

Relapsing polychondritis is a systemic disease of unknown cause in which various inflammatory reactions recur in the cartilage structures of the ears, nose, and trachea (Kaye & Sones 1964). Although the cause of this disease is unknown, several immunologic abnormalities have been noted which explain some of the pathogenic mechanisms involved (Dolan et al. 1966, Herman & Dennis 1973, Rajapakse & Bywaters 1974, McKenna et al. 1976, Bergfeld 1978, Foidart et al. 1978). To ascertain if the frequency of HLA antigen is increased among patients with this disease, we performed HLA-A and HLA-B locus typing in Caucasian patients with well documented disease. Serologically defined HLA antigens at the A and B loci were determined by the microcytotoxicity assay of Mittal et al. (1968). No statistically significant increase in the frequency of any of the HLA-A or B locus antigen type was found between the patient group and the control group (Table 1). These findings suggest that no correlation exists between HLA-A and B locus antigens and relapsing polychondritis. HLA-DRw antigen typing was not done, although such typing would be of interest.

We have reported that heart transplant recipients treated with pravastatin demonstrate decreases in the incidence of clinically severe acute rejection episodes, the incidence and progression of transplant coronary vasculopathy, and natural killer cytotoxicity. These patients also exhibited a significant improvement in 1-year allograft survival. Because of these clinical findings suggesting an immunosuppressive effect of pravastatin unique to transplant recipients and the unclear role of natural killer cells in allograft rejection, we postulated that pravastatin may exert its immunomodulatory effect by acting with cyclosporine to alter T lymphocyte function.Twenty patients randomized into an ongoing trial of pravastatin after heart transplantation were monitored serially for natural killer cell cytotoxicity. In a separate experiment, lymphocytes isolated from normal volunteers were treated with various combinations of pravastatin and cyclosporine and tested for cytotoxic T lymphocyte toxicity in a one-way mixed lymphocyte reaction.Pravastatin-treated heart transplant recipients exhibited a decrease in natural killer cell cytotoxicity (9.8% mean natural killer cell cytotoxicity vs 22.1% in the control group, p0.01). In the one-way mixed lymphocyte reaction with blood obtained from control subjects, there was a synergistic inhibition of cytotoxic T lymphocyte activity when the cells were cultured in a combination of pravastatin and cyclosporine (20.3% mean cytotoxicity of target cells vs 41.4% in the control group, p0.01).Pravastatin exerts an immunosuppressive effect in heart transplant recipients as expressed by a reduction in rejection and natural killer cell cytotoxicity. Pravastatin and cyclosporine act synergistically to reduce cytotoxic T lymphocyte activity. This synergistic effect of pravastatin and cyclosporine may explain why this immunosuppressive effect is unique to transplant recipients.

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.

Numerous allocation schemes have been proposed. The most important feature they have in common is providing a rationale of why one patient receives the kidney, and 35 000 others do not. In the United States in 1998 some 20 000 patients may wait in vain for, despite having a chance to obtain a kidney, they could not … simply because there were not enough kidneys to satisfy the demand. As the disparity between the number of waiting patients and the number who actually receive a kidney widens, allocation formulas become more and more overbearing. Ideally, allocation should be based on what combination would result in the best long-term medical outcome for the patient. As long as the kidney shortage problem continues to worsen, allocation tends to become more and more influenced by extraneous factors, such as donating center points, distance to patient, waiting time, etc.

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.

1. Donor age is now a predominant factor influencing graft outcome. 2. A new finding here is that recipient peripheral vascular disease, PVD is also a major factor. This factor was independent of whether the patient had diabetes or not. Presensitization, as shown by a high PRA is additive to PVD. 3. Hypertension in the donor was important only when a history of more than 10 years was noted in the older donors over age 50. 4. Angina and cardiovascular disease in the patient resulted in a slightly higher death rate, but was only of importance in patients over age 50. 5. Cadaver donor pretreatment was of importance only in donors over age 30. 6. White patients with private insurance had a slightly higher graft survival rate than those on Medicare or Medicaid. Black patients with private insurance had almost the same graft survival as White patients with private insurance. The lowest graft survival was noted for Black patients on Medicaid.

Due to the shortage of cadaver donor kidneys in the US, an increasing effort has been made to supplement the donor supply with transplants from unrelated living donors (URLD). In the present communication, we wish to update the URLD results from the United Network for Organ Sharing (UNOS) Kidney Transplant Registry. Since we last published the results, the number of such transplants has more than doubled.

1. We anticipate that the number of kidneys from conventional heart beating donors who are under age 55 will remain stable at about 8,000/year. A natural increase of donors over age 55 and living donors is expected to increase the total transplants from about 12,000 today to 14,000 in 8 years. 2. We propose a 4-year acceleration phase, during which older cadaver donors, related and unrelated living donors will be increased to a maximum of 4,000 in the 4th year. This acceleration is a temporary one, and will be reduced to zero over 4 subsequent years. 3. An increase in NHBD will be encouraged at a rate of 700/year, so that at the end of 14 years, they would constitute about 10,000 cadaver donor kidneys. As can be seen in Figure 1, at this rate, NHBD kidneys will first replace the accelerated effort, then replace the living donors and eventually the older heart beating donors. With the abundance of kidneys, it is likely that many patients who are not listed today would be encouraged to become transplant candidates. Moreover, patients needing retransplants will increase. However, once this capacity is developed, any increases in new transplant candidates could be accommodated. Thus in 14 years, there will be about 18,000 kidneys available each year. Approximately 60% will be NHBD and 40% heart beating donors, with no living donors and no older donors and no need of pig donors. We will be in transplant nirvana.

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).

This study was designed to determine the frequency of hyperlipidemia after orthotopic liver transplantation and whether treatment with a hydroxy-methylglutaryl coenzyme A reductase inhibitor was safe and efficacious. Cholesterol levels were assessed in 45 consecutive adult liver transplants (mean +/- SE). Four of 22 patients on cyclosporine (CsA) (18%) and three of 23 patients on FK506 (13%) had levels225 mg/dl at 12 months (cholesterol levels for patients on CsA [total n=22]: pre-Tx = 140+/-11, 1 month = 183+/-36,3 months = 221+/-12, 6 months = 211+/-11, 12 months = 202+/-14 [P0.01 vs. pre-Tx]; FK506 [total n=23]: Pre-Tx = 151+/-13, 1 month = 187+/-22, 3 months = 188+/-10, 6 months = 184+/-13, 12 months = 164+/-9 [P=0.02 vs. CsA]). A separate cohort of patients with stable graft function, cholesterol225 mg/dl, and two additional risk factors for coronary artery disease were started on pravastatin. Ninety-eight patients were enrolled. Sixteen patients (16%) discontinued the drug because of subjective complaints. No episodes of rhabdomyolysis or hepatotoxicity occurred (cholesterol levels for patients on CsA [total n=65]: pretreatment = 251+/-7, 6 months = 220+/-7 [P=0.01 vs. pretreatment], 12 months = 224+/-8 [P=0.01 vs. pretreatment]; FK506 [total n=17]: pretreatment = 251+/-17, 6 months = 219+/-17, 12 months = 208+/-17 [P=0.08 vs. pretreatment]). Natural killer cells isolated from normal volunteers (n=14) exhibited 27+/-9% specific lysis. Patients on FK506 or cyclosporine-based immunosuppression alone (n=11) exhibited 20+/-4% specific lysis. Standard immunosuppression plus pravastatin (n=10) decreased lysis to 0.2+/-10% (P0.02 vs. controls and standard immunosuppression). We conclude: (1) posttransplant hyperlipidemia occurs less frequently in liver transplant patients than in renal or cardiac transplants; (2) pravastatin is safe and efficacious for cholesterol reduction in liver transplant patients; and (3) pravastatin coadministered with standard immunosuppression reduces natural killer cell-specific lysis in these recipients.

The importance of HLA matching for cadaver-donor transplants is often ignored due to the small (10%) difference in graft survival rates between the best and worst matched pairs. A new "fit and match" hypothesis is proposed to improve the predictive value of matching. Graft and functional survival rates of kidney transplants were calculated for living and cadaver-donors by the standard Kaplan and Meier methods. Mean discharge serum creatinine (SCr) values were computed after excluding patients who died or lost their grafts before discharge. Donor size, recipient size, age of donor kidney, damage caused by cold ischemia time, and mode of donor death all had substantial effects on the average SCr levels at discharge. These SCr levels correlated with one- and five-year graft survival rates. Transplants that had extremely different graft survival rates, such as those from living donors and cadaver donors, were found to have similar rates when reclassified by SCr levels at discharge. By examining the combined effects of the fit and match factors, transplants with the best fit and match exhibited a 95% one-year graft survival rate, whereas those with the worst fit and match had a 75% survival rate. This 20% difference increased to 36% after five years (84% vs. 48%). We conclude that the fit and match hypothesis provides a theoretical basis for devising a more critical method of predicting cadaver kidney transplant survival rates. Furthermore, it suggests a vital need to develop methods for estimating functional donor renal mass.

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.

Whether patient deaths among renal transplant recipients should be counted as transplant failures when they occur while the transplant is still functioning is a controversial issue. Analyses of more than 45,000 first cadaver transplants reported to the UNOS Scientific Renal Transplant Registry between October 1987 and March 1995 showed that deaths among transplant recipients were strongly associated with the patient's age and presence of insulin-dependent diabetes. Other factors associated with poor early graft function were also associated with a significantly increased risk of death. Deaths within the first 5 years increased from 9% of recipients aged 2-15 to 30% of those over age 45 (P0.001). Deaths with a functioning graft occurred in 2% of the youngest patients and 13% in the older age group (P0.001). Among diabetics, 32% died within 5 years (12% with a functioning graft) compared with 10% (6% with graft function) of patients with glomerulonephritis (P0.001). When the transplanted kidney failed to function immediately or the patient required dialysis during the first week after transplant, 30% of patients died within 5 years compared with 20% when the graft functioned (P0.001). There was no difference in the percentage of deaths with a functioning graft. We conclude that deaths among renal transplant recipients follow an expected pattern in which the likelihood of death increases with age and diabetes.

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]

As reported to the UNOS Kidney Transplant Registry from 1988 through 1994, 544 first cadaveric kidney graft recipients have been discharged with maintenance tacrolimus (FK506) therapy. Total follow-up data was available on 38,057 first cadaveric kidney transplants from 224 centers reporting at least 10 grafts each to the Registry. We examined the effects of FK506 on short- and long-term renal graft outcomes and compared its effect with that of cyclosporine (CsA). Three drug categories (FK506, CsA, and Other) were defined using therapies through discharge (i.e., grafts surviving more than 15 days). The 1-year graft survival rate of 2366 recipients receiving Other therapies was 69.2 +/- 1.0%. By comparison, both FK506 and CsA recipients demonstrated significantly improved early graft function (1-yr survival rates of 91.1 +/- 1.3% and 86.6 +/- 0.2%, respectively). The long-term graft survival, as measured by half-lives, varied little (8-9 yr) between Other and CsA groups, but was significantly (P = 0.04) increased for FK506 patients (to approximately 14 yrs). CsA usage was reported by all 224 transplant centers, whereas FK506 was administered at only 24 (11%) centers. Using multivariate methods, a drug regimen's graft survival rate was adjusted for center effects and 19 covariates. The adjusted FK506 and CsA cadaveric graft survival rates at 1 and 3 years mirrored their unadjusted rates, indicating that demographic differences did not confound our results. Based on this study, FK506 appears to be the first therapeutic agent to significantly improve long-term kidney graft survival rates.

Graphs and tables published 10 years ago in our Clinical Kidney Transplants 1985 book are compared to current analyses. Impressive progress is apparent over the past decade. During this period, the effects of factors such as transfusion and the duration of first grafts on second grafts have disappeared, while the effects of factors such as cold ischemia time, regrafts and original disease have diminished in magnitude. Other factors, including HLA matching, donor age and race, continue to exhibit significant influence. It should be emphasized that most of these comparisons apply to one-year graft survival. Thus, our attention must now turn to factors which influence 10-year graft survival. Though 10 years is considered long-term survival to transplant physicians, for patients, it is but a brief period of life.

Several new factors collected by UNOS since 1994 were examined with regard to their effects on early graft function and 6-month graft survival in this study. Medicare patients had a lower 6-month graft survival rate than private insurance patients, though the difference was not statistically significant. Medicaid patients had a significantly lower graft survival rate than private insurance patients (p=0.04). Blacks had the same graft survival as Whites when they had comparable coverage. Both Blacks and Whites had higher graft survival with private insurance and lower survival with government funding. Non-heartbeating cadaver-donor kidneys yielded a lower graft survival rate than heartbeating donors (p=0.03). Experience with non-heartbeating donors is just beginning with only 89 kidneys compared with 8,766 heartbeating donor kidneys. Kidneys from donors with hypertension resulted in lower graft survival rates than those from donors without hypertension (p=0.01). In these preliminary studies, donor history of diabetes, smoking, alcohol dependency, I.V. drug use and cancer did not have a significant impact on graft survival. Patients who had a high body mass index (26) had a lower 6-month graft survival rate (p=0.009). Patients who received kidneys from cadaver donors with a low body mass index (20) had a lower 6-month graft survival rate (p=0.02). When the recipient was more than 30 kg heavier than the donor, a lower 6-month graft survival rate was obtained (p=0.007). When the weight ratio was greater than 2.0, again a lower survival was noted (p0.001). A recipient-to-donor height ratio of more than 1.25 resulted in an 80% 6-month graft survival which was significantly less than the 87% survival rate among those with a ratio less than 1.25 (p0.001). This cut-off was found to identify patients with the lowest 6-month survival rate, suggesting that donor-recipient pairs with a height ratio above 1.25 should not be transplanted. A 6-month graft survival rate of 90% was reported with a SMI of 16-20, where SMI = weight of recipient divided by the square of the donor height. From this preliminary study, the SMI appears to be the best predictor of high graft survival since 1,450 patients were in this category with a 90% survival at 6 months.