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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.

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.

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.

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.

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.

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.

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.

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).

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.

The hyperfiltration hypothesis postulates that kidneys with reduced renal mass will progress toward failure due to hypertrophy of the remaining nephron to meet the excess load, eventually leading to nephron exhaustion. Five conditions in which hyperfiltration might be suspected were studied in human kidney transplantation: (1) small kidneys from donors aged 4 to 6; (2) transplants into large recipients (over 100 kg); (3) grafts from females to males compared with males to females; (4) kidneys that experience rejection episodes; and (5) cadaveric grafts compared with living-unrelated donor grafts. In all 5 instances, the requirement for dialysis and discharge serum creatinine level were both high--and, correspondingly, the 1- and 3-year graft survival rates were lower than the controls. The discharge SCr was the best indicator of 1-3-year graft survival and may serve to measure the "fit" of the kidney to the recipient--for even in patients requiring no dialysis graft survival was related to the discharge SCr levels. One consequence of this hypothesis is that many late graft losses currently attributed to rejections may, in fact, be hyperfiltration failures. As evidence, a progressively higher incidence of reported late rejections was noted even in patients who had been rejection-free at the time of discharge if they had higher discharge SCr values. We conclude that the 5 conditions under which hyperfiltration damage might be suspected had increased failure rates. Such failures are almost never reported as "due to hyperfiltration" and are probably recorded as rejections.

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.

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.

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.

Overall one-, 5-, and projected 10-year graft survival rates were 81%, 58% and 39%, respectively for 51,442 cadaveric kidney transplants performed at 251 U.S. transplant centers from October 1987-December 1994. The comparable results for recipients of living donor kidneys were significantly higher, 91%, 75%, and 60% (p0.001). One-year first cadaver graft survival rates improved from 77% for transplants performed in 1987-1988 to 84% for transplants performed in 1991-1992 (p0.001). Recipients of second cadaveric transplants in 1987-1988 had a 69% one-year graft survival rate compared with 81% for those transplanted after 1990 (p0.001). Graft survival rates have been stable since 1991. The percentage of broadly sensitized first transplant recipients decreased from 13% before 1991 to 7% after, and the one-year graft survival rates increased by 4-6% for both sensitized and nonsensitized recipients between the 2 periods (p0.001). Among retransplanted patients, the percent of broadly sensitized recipients fell from 40-33% over the same periods (p0.01). One-year graft survival rates increased by 7-8% for sensitized and nonsensitized patients (p0.001). One-year graft survival rates improved from 74-83% for Blacks (p0.001) and from 78-85% for non-Blacks (p0.001) transplanted for the first time when comparing transplants performed in 1987-88 with those performed in 1993-94. The cause of donor death had a significant effect on graft survival. The 5-year graft survival rate was 61% for 28,923 recipients of trauma donor kidneys compared with 54% for 16,956 transplants from CVA donors (p0.001). Kidneys from CVA donors increased from 28% of all cadaveric kidneys in 1988 to 38% in 1994. The donor's age was a more important determinant of long-term survival, however, and correlated strongly with the cause of donor death. Only 16% of CVA donors were reportedly age 30 or less, compared with 75% of trauma donors. First cadaver graft survival decreased by approximately 2% for each 12 hours of cold ischemia time. Although there was a significant increase in the incidence of delayed graft function from 19% when the CIT was less than 12 hours to 35% when the CIT was more than 36 hours, there was no significant long-term effect of cold ischemia time. The recent change in UNOS policy to share zero-HLA mismatched kidneys resulted in a 2-fold increase (from 8%-16%) in the number of HLA-matched transplants performed during the first 6 months following the change. The percentage of Blacks who have received matched kidneys following this change has increased from less than 2% to more than 5%, a 3-fold increase. The 163 Blacks who received an HLA-matched kidney prior to 1995 had a 65% 4-year graft survival rate compared with 53% for mismatched Blacks (p0.001). The incidence of early rejections was also reduced by 25% among matched recipients and the graft half-life was 8 years compared with 5 years for mismatched Blacks. About 25% of HLA-matched kidneys were transplanted to ABO compatible but not identical recipients. Although the effect of the policy allowing compatible transplants did not result in a large number of type O kidneys transplanted to non-O recipients when only 8% of kidneys were shared, the recent change in allocation policy may be detrimental to type O waiting patients.

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%.

1. First cadaver-donor recipients had a 7% death rate if the kidney originated from a CMV+ donor compared with 5% if the kidney came from a CMV-donor. This 2% difference was highly significant (p0.001). Graft survival rates were correspondingly 2-3% lower as a result of deaths. 2. This same trend was noted in the 1991-1993 period as in the 1988-1990 period. 3. Increased incidence of deaths in D+/R+ transplants was most frequently statistically significant when patients were divided by early function. 4. Death rates in diabetics rose from 7% in D-/R- combinations to 13% in D+/R- patients (p0.001). Patients with other diseases did not show as marked an effect. 5. Among kidneys from living-related donors, there was no noticeable effect of donor CMV status. Thus, for these donors, no precautions need be taken regarding CMV status. Spousal-donor transplants had a higher graft survival if a D-/R- rather than other combinations were used. 6. The incidence of CMV positivity was slightly higher in Black patients compared with Caucasians, in females compared with males, and increased progressively with age. CMV positivity increased in patients with multiple grafts, presumably because transplanted patients increased in CMV positivity. Among patients who were on dialysis, the CMV positivity was higher than in donors of cadaver organs. There was a substantial difference in CMV positivity in different areas of the country, ranging from 36% in Ohio to 65% in Washington. 7. The HLA matching effect was greater than the CMV effect, justifying its use as the main prospective factor in kidney allocation. CMV prophylaxis is needed for patients receiving kidneys from CMV+ donors. The data indicate that, whenever possible, CMV+ donor kidneys should not be used for CMV- IDDM patients.

1. In 1984, second graft survival rates were 10% lower than first grafts, but in 1992, the survival difference was reduced to 1%. Multiple grafts in 1984 were 23% lower than first grafts, but showed only a 7% difference in 1992. In 1992, 12% of kidney grafts were performed into second graft recipients and 3% into multiple graft recipients. 2. If first grafts survived one to 12 months posttransplant, the second graft survival was less than if they had survived longer than 12 months, as seen in many previous analyses. Here we showed that patients with a first graft duration of one to 12 months had a higher incidence of sensitization than patients with a first graft duration of more than 12 months. This may indicate that immunization was the cause of failure more frequently among those patients who rejected earlier than later. 3. Since 1989, the interval between first graft rejection and second graft transplantation was not a factor in second graft survival. A strong correlation was noted between high PRA and interval to regrafting. This probably reflects the increasing difficulty in finding negative-crossmatch donors as PRA increases. 4. Repeat mismatches for HLA-DR were deleterious to second grafts, although repeat mismatches for HLA-A,B were not, confirming earlier studies (1,5). HLA-A,B,DR mismatches correlated well with second and multiple transplant outcomes. 5. Patients receiving second cadaver-donor transplants had the same graft survival regardless of whether the first graft was another cadaver donor or a living-related one. On the other hand, second living-related donor transplants had a higher graft survival rate if the first graft had also been from a living-related rather than a cadaver donor (p0.05). This suggests that it would be advantageous if the first graft came from a living-related donor with a cadaver donor as the second graft, rather than the reverse situation. 6. Urine production on the first postoperative day was a very strong indicator of subsequent graft survival, particularly for second and multigraft patients. Failure to diurese on the first day resulted in a second graft survival of 60% at one year compared with 80% for those that diuresed on the first day. 7. Similarly, dialysis requirements were a major factor in predicting subsequent graft survival. For second graft patients who required dialysis, one-year graft survival was 63%, compared with 84% if no dialysis was needed. 8. The fraction of patients who had insulin dependent diabetes for first grafts was 27%, 15% for second grafts, and 9% for multiple grafts.(ABSTRACT TRUNCATED AT 400 WORDS)

1. Approximately half of the pediatric patients received grafts from their parents and half from cadaver donors. Pediatric recipients accounted for only 5% of cadaver-donor transplants. 2. Pediatric patients differed from adults in the incidence of primary disease, principally in the occurrence of diabetes (almost no juvenile diabetics had progressed to renal failure compared with 30% among adults). Obstructive uropathy and dysplasia were the primary diseases for about 37% of pediatric patients compared with 3% in adults. 3. Pediatric patients under the age of one had a markedly lower graft survival with cadaver donors. Such patients had much higher survival rates with parental donor kidneys. 4. Pediatric retransplants from parents had a graft survival comparable to adult grafts. Regraft survival in children given cadaveric kidneys were significantly lower than adult grafts. 5. Patients under the age of 18 with no diuresis on the first day or who required dialysis in the first week had a markedly lower graft survival rate compared with that of adults with comparable early dysfunction. 6. Kidneys from donors under 2 years old yielded a 67% one-year graft survival rate in infants, but an 87% survival in patients 16-18 years of age at 6 selected individual centers. These centers, that had performed more than 20 infant-donor renal transplants, achieved results comparable to those of transplants using grafts from older donors in recipients aged over 11 years. 7. Pediatric patients who received grafts mismatched for 5- and 6-HLA antigens had a significantly lower graft survival rate than those with better matches. 8. Black patients ages 11-18 years old had a lower graft survival rate than White patients in the same age group.

1. Graft survival was similar at one year for the various diseases, but at 3 years, a 16% divergence was noted among diseases. IGAN patients had the highest graft survival rate. 2. Graft survival rates of IGAN, ALP, and PC in Black and White patients were similar, but in all other diseases, a high loss rate was seen after one year among Black patients. 3. Patient survival was almost identical for the various diseases among Whites and Blacks. 4. SLE patients with DR2 or DR3 had higher graft survival rates than SLE patients without these groups (p0.05 in Whites). 5. IDDM patients with DR3 or DR4 had higher graft survival rates than IDDM patients without these groups (p0.05 in Whites, p = ns in Blacks). 6. Nephrosclerosis patients with DR2 or DR4 had higher graft survival rates than those who did not (p = ns in Whites, p0.05 in Blacks). 7. CGN patients with DR1 had higher graft survival rates than CGN patients without DR1 (p0.00005 in Whites). 8. IDDM patients with SPK transplants had higher graft survival rates than IDDM patients grafted with a KAT (p0.000001). In recent years, almost 30% of IDDM patients had SPK transplants. 9. Patients with SPK grafts compared to KAT were younger, White, were more often DR3/4, and worked full-time. 10. The SPK effect was seen only at the excellent centers. At all other centers, SPK and KAT patients had the same graft survival rates.

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.

1. The one-, 3-, and projected 10-year graft survival rates for the 35,741 first cadaveric transplants reported to the UNOS Registry were 81%, 69%, and 40%, respectively. The corresponding results of transplantations from parent donors were 90%, 81%, and 54%, and from HLA-identical siblings, 95%, 90%, and 74%. 2. Graft survival rates have improved significantly since the Registry began collecting data in October 1987. Between 1988 and 1991, survival of first-cadaver transplants rose from 77% to 84% (p0.001), while that of second transplants increased from 69% to 80% (p0.001). Some of the increase in graft survival rates was attributed to a 4-5% improvement in patient survival over the same interval. 3. Graft survival also improved among recipients of living-donor transplants. Overall survival increased from 88% in 1988 to 93% in 1991 (p0.003), although the results for 1992 suggest 92% may be a better expectation. The approximately 4% rise was distributed among recipients from each of the major donor relationships: HLA-identical siblings (3%); one-haplotype-matched siblings (8%); and parents (4%). Patient survival improved by one to 3%. 4. Transplants between spouses and those between distant relatives or other unrelated donors yielded excellent results. Graft survival rates at one and 3 years for 284 spousal-donor transplants were 92% and 85%, respectively. The corresponding results for 533 patients transplanted from distant relatives or other living donors were 91% and 84%. In each case, the results were higher than those for transplants from parents to their children (though the difference was not statistically significant). 5. Antilymphocyte antibodies (ALG/ATG/OKT3) given prophylactically resulted in up to a 4% improvement in graft survival rates for recipients of first-cadaver transplants. Patients who received a kidney mismatched at one or 2 HLA antigens had a 2-10% higher graft survival rate each year than those mismatched at 5 or 6 antigens. 6. HLA matching resulted in higher graft survival rates for Whites, Blacks, and Asians. Among Whites, where there was a large number of well-matched transplants, 3-year graft survival was 84% with no mismatches, and 75%, 71%, and 67%, with one or 2, 3 or 4, and 5 or 6 mismatches, respectively. Each decrease in 3-year survival was significant (p0.001). Among Blacks and Asians, the rankings showed a similar trend although the number of well-matched patients was small in each race.(ABSTRACT TRUNCATED AT 400 WORDS)

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.