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

1. 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. 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 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.

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.

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.

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.

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

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

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. 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. 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.

The importance of HLA histocompatibility typing to the outcome of transplantation of cadaveric kidneys has been controversial. Four years ago, a prospective trial began in all U.S. transplantation centers to determine whether the results of transplantation would improve with the nationwide shipment of kidneys from cadaveric donors to waiting patients undergoing dialysis when there was a match at the HLA-A, B, and DR loci.A total of 1386 cadaveric kidneys were shipped from 108 organ centers to 198 transplantation centers and distributed among HLA-matched recipients, 1004 of whom were receiving a first transplant and 382 of whom were receiving a subsequent transplant. Graft survival in these recipients was compared with that in 22,188 recipients of first transplants and 3950 recipients of subsequent transplants whose HLA antigens differed from those of the donor.The rate of graft survival at one year in recipients of HLA-matched first transplants was 88 percent, as compared with 79 percent in the recipients of mismatched grafts (P less than 0.001). The estimated half-life of the kidney after the first year was 17.3 years for matched grafts, as compared with 7.8 years for mismatched grafts (P = 0.003). Among paired kidneys from 470 donors, one-year graft survival was 87 percent in the recipients of matched first grafts, as compared with 80 percent in the recipients of the contralateral kidneys, who did not have HLA matches with the donors. In donors and recipients matched for the more highly defined split Class I and Class II HLA antigens, the rate of graft survival after one year was as high as 90 percent.The collaborative renal-transplantation program for HLA matching of donors and recipients yielded an increased rate of one-year graft survival and an estimated half-life for matched grafts twice that for mismatched grafts. An increased role for HLA matching in kidney allocation is therefore indicated.

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 Renal Transplant Registry from more than 200 centers nationwide. Graft survival rates at 1 year differed by 20-30% depending upon whether or not the transplanted kidney functioned immediately and upon whether the patient required dialysis during the first week posttransplant, experienced rejection, or was discharged with a kidney that was functioning well. Recipients whose discharge serum creatinine level was less than 2.6 mg/dl or whose graft was functioning well at the time of discharge had 88% 1-year graft survival. A multistep logistic regression analysis showed cold ischemia time, transfusions, donor age and cause of death, HLA-DR mismatches, and peak sensitization to be significant factors in the first week. Prophylactic antilymphocyte antibodies (ALG/OKT3) reduced the incidence of rejection from 30% to 20% during the transplant hospitalization, but apparently only delayed rejection. By 6 months there was only a 3% reduction with ALG and a 5% reduction with OKT3 in the incidence of reported rejection and a 2% difference in 1-year graft survival. Although graft and patient survival are important measures of transplant success, graft survival is predicted upon both early and late events. The course of the transplant during the initial hospitalization and the quality of function at discharge were the strongest determinants of 1-year graft survival.

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

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

1. The transfusion effect, which was apparent in 1981, disappeared in 1988, and reversed itself in 1990. In other words, for the first time, transfused patients have started to have lower graft survival rates than nontransfused patients. 2. The proportion of transfused to nontransfused patients has decreased from a ratio of 10:1 in 1981 down to 1:1 in 1990. 3. The transfusion effect in related donors has also disappeared in recent data. 4. Data revealed that HLA-A,B, and DR mismatching had no effect between 1988 and 1990. 5. A small transfusion effect continues to be seen in young recipients. 6. In earlier data, the transfusion effect was most marked in Blacks and Hispanics, but the reverse trend is now shown for these races. White recipients had exactly the same survival rates with and without transfusions. 7. Sensitization occurred more often with transfused patients who had a tendency toward slightly lower graft survival. This was true in males, females, and pregnant females. 8. Recipients who waited on dialysis for more than 2 years had slightly lower graft survival and data showed they had received more transfusions. 9. The loss of the transfusion effect occurred at both large and small centers. The centers with 1-year graft survival under 70% tended to have a transfusion effect, whereas those above 70% had either better or worse results with transfusions.

1. Two-step Cox regression analyses showed that, for White recipients of first cadaver transplants, pretransplant transfusions, HLA-DR mismatch, donor race, CIT, size mismatch, PRA, old donor, and recipient age were significant prognostic factors during the first 6 months posttransplant, and after that, older donor, CIT, and size mismatch continued to have effects on graft survival in the longer term. 2. For African-American recipients of first cadaver transplants, pediatric donor, cause of donor death, and increasing second warm ischemia time were major risk factors in the early period, but in the late period, the effect of donor age dominated other factors. 3. Multistep linear logistic regression and two-step Cox regression analyses yielded similar results, with donor-related and histocompatibility factors dominating survival outcome in both the short and long terms.

We reviewed 14,005 renal grafts with the temporal opportunity for 10-year survival (transplanted 1975 and earlier) and analyzed 10-year actuarial graft survival and the rate of late (3- through 10-year) graft loss as reflected by half-life. The 10-year graft survival for first transplants in HLA-identical siblings was 67% versus 38% for parental donors and 20% for cadaver donors. Factors with substantial influence on 10-year graft survival include transplant number, transfusions (0, 17%; greater than or equal to 1,33%), HLA-A,B mismatches (0, 29%; 1-2, 20%, 3-4, 17%), cold ischemia time (0-3 hours, 32%; 4-6 hours, 27%; 7-12 hours, 21%; greater than 12 hours, 16%), preservation method if CIT is no more than 24 hours (cold storage, 22%; machine, 17%), recipient race (Caucasian, 23%; black, 11%), original disease, recipient age, recipient sex, donor race, and the quality of early graft function (less than or equal to one month). Factors not significantly influencing 10-year graft survival were panel-reactive antibodies, warm ischemia time, preservation method if CIT was more than 24 hours, and donor sex.(ABSTRACT TRUNCATED AT 250 WORDS)

1. Kidney graft survival rates have stabilized over the past 4 years, suggesting that gains achieved with CsA have plateaued. The overall 1-year graft survival is 77% for first cadaver donor transplants, 90% for parental donors, and 93% for HLA-identical sibling donors. Patient survival for all categories is now over 95%. 2. The UNOS 6-antigen match program has resulted in outstanding graft survivals. Of 88 kidneys which were transplanted into first graft recipients, the 6-antigen match kidney had a 1-year graft survival of 91% compared to 74% for the contralateral kidney transplanted locally (p less than 0.008). 3. In highly sensitized patients with more than 80% PRA the shipped 6-antigen matched kidney had a 91% 1-year graft survival rate compared to 72% survival in comparable control patients from the registry (p less than 0.005). In patients with less than 80% PRA, 6-antigen matched kidneys had 90% 1-year graft survival compared to 80% in controls (p less than 0.00001). 4. The spread of 1-year graft survival rates at 68 centers that performed more than 100 transplants was 63-94%. The cumulative graft survival of 6-antigen matches performed at 129 different centers was 90%. Thus, the strong center effect was neutralized by the use of matched transplants. 5. In contrast to the 1% of patients who would receive O-B,DR mismatched transplants on a random basis, if kidneys were shared in the national pool, 74% could receive such a transplant. We therefore propose that a keep one-share one policy be adopted for all kidneys harvested in the United States. If no 0-B,DR mismatched patient is available, both kidneys will be kept by the harvesting center. Since 63% of kidneys are currently being shared with other centers for various reasons, the 75% sharing suggested by the new system should not impose a hardship on transplant centers. The UNOS payback agreement will be replaced by this agreement by which shipping will be done only to achieve excellent matches. 6. In order to achieve a better method of excluding the worst mismatches, an attempt was made to develop a new method of mismatching using amino acid sequences of the HLA specificities. Donor and recipient types can be converted to amino acid sequences and the mismatching done on the basis of amino acids of mismatch at each residue or position. For each residue, specific combinations of amino acid substitutions were examined individually to determine their effect on graft survival. From these studies, a list of "immunogenic" amino acids was prepared, and graft survival was then computed for increasing numbers of amino acids of mismatch.(ABSTRACT TRUNCATED AT 400 WORDS)

1. There was a "transfusion effect" for cadaver kidney transplant recipients and the improvement of 1-year graft survival with transfusions was 7.1% (p0.0002) in 1987. 2. Two or 3 pretransplant transfusions are sufficient to obtain the maximum transfusion effect. 3. In 1988, about a quarter of the patients received first cadaver kidney transplants without any pretransplant transfusions, whereas only 10% were nontransfused during the period between 1981 and 1984. 4. The transfusion effect diminished as patients aged. The increase in 1-year graft survival with transfusions was 17% in patients aged 16-25, 4% in patients aged 46-55, and 1% in patients over 55. 5. Both transfused and nontransfused patients had as high as 83% 1-year graft survival rates when they received 0 A, B, DR-mismatched kidneys. Transfusions improved graft survival by as much as 8% for recipients with mismatched grafts. 6. There was no transfusion effect in recipients of 0 DR-mismatched kidney transplants. Transfusions improved the 1-year graft survival rate by 8-10% for transplant recipients with 1 or 2 DR-mismatched kidneys. 7. The transfusion effect was greater in black (8%) than white (4%) recipients; however, the 77% 1-year graft survival rate for transfused black recipients of 0 DR-mismatched kidneys did not differ from that of transfused whites. 8. Considering the transfusion effect on graft failure rather than graft survival, the failure rate in nontransfused patients could have been reduced by 30% in transplants performed between 1976 and 1979, 17% in transplants from 1980 through 1983, and 21% in transplants since 1984 with blood transfusions.

Among 53 patients with documented Crohn's disease, 30% manifested a defect in delayed hypersensitivity demonstrated by negative DNCB skin tests and significant (p less than 0.01) T-lymphocyte hyporeactivity. A double-blind controlled trial was conducted to evaluate oral Bacillus Calmette-Guerin (BCG) therapy in nine of these patients with Crohn's disease and deficient cellular immunity. All patients had a Crohn's Disease Activity Index (CDAI) greater than 150 (at least moderate activity) upon randomization to BCG (five patients) or placebo (four patients) treatment for six to 12 months. No significicant differences between BCG and placebo treatment were found in the CDAI, laboratory tests and gastrointestinal roentgenograms. We conclude that the disturbance in cell-mediated immunity in patients with Crohn's disease probably is a manifestation of the disease rather than an etiological factor and that immunostimulation with oral BCG is not effective therapy.

For some 20 years a coordinated arrangement for sharing cadaver organs has been in place in Southern California. It's 11 transplant centers have performed 4,947 kidney transplants from 7,480 referred donors. There were 430 transplants done in 1985. The policy has been to keep one kidney and share the other within the pool. This has resulted in a better than average level of matching for HLA, and an overall better than average graft survival. The graft survival rates at the centers have been increasing yearly. Much of the improvement in graft survival resulted from the introduction of cyclosporine, but a summation of many factors contributed to a steady yearly increase. There are some 600 patients waiting for transplantation. With greater efforts in procurement of cadaver kidneys, especially from minorities, and continued collaboration between the transplant centers, it should become possible to transplant all those who are in need of a kidney.

1. In 9 yearly cohorts from 1978 to 1986, male and female recipients had the same one-year graft survival rates for first cadaver donor grafts. For regrafts, female recipients had superior survival in 2 out of the 9 years. 2. In contrast, in the same 9 yearly cohorts, female donor first cadaver grafts had a lower survival than male donors in 8 out of the 9 comparisons, although the difference was not statistically significant. For regrafts for the last 5 years, in 4 different years females had a statistically significant lower graft survival rate compared to males. 3. The lower survival rate of female donor kidneys was especially evident in the CsA-treated regrafted patients, although a similar tendency was noted also in non-CsA-treated regraft patients. 4. Grafts from females older than 30 years had the lower survival rate in the regrafted patients. 5. The depressed survival effect of female donor kidneys was not affected by the recipient's sex or original disease. 6. Female donors kidneys from either trauma or nontrauma donors yielded lower survival rates. Thus, the cause of death in the donor is probably not the principal explanation for the donor sex effect. Since males more often die from trauma, it was initially thought that the sex effect could be attributed to the difference in mode of death of the donor. 7. Regrafts from living-related female donors who differ by one HLA haplotype had a lower regraft survival rate than grafts from male donors. 8. It is unlikely that a sex-associated histocompatibility antigen exists in the clinical kidney transplant situation since females who received 2 grafts from male donors had a statistically significant superior survival to females who received 2 successive grafts from female donors. Thus, rejection of a male graft by a female does not sensitize the recipient to a second male graft, and second female grafts when the first was a female result in a lower graft survival. 9. Poor mismatches for HLA-A, B, or DR antigens were more deleterious with female donors than male donors. With CsA, the lower regraft survival with female donors was statistically significant in all categories of DR mismatches. 10. Transfusions did not influence the donor sex effect. The level of panel reactive antibody also did not affect the lower survival of female donor kidneys. 11. The donor sex effect was apparent in first grafts and regrafts even one month after transplantation.

Donor age. 1. Kidneys from older donors led to markedly lower graft survival than kidneys from younger donors. The 1-year first cadaver donor graft survival rates were 80% for recipients receiving kidneys from 16-year-old donors, 70% from 50-year olds and 57% from 65-year-old donors. This means that 1-year graft survival decreased 10% by donor age 50 and 23% by donor age 65. 2. The trend toward lower graft survival with older donors was most noticeable after 1985, suggesting that CsA treatment was primarily responsible for the effect. 3. Twelve percent of kidneys from donors over age 50 never functioned while the nonfunction rate of 17- to 30-year-old donor kidneys was only 2%. Forty-six percent of kidneys from younger donors functioned within 3 days, whereas 26% functioned in 3 days if they came from donors who were older than 50. 4. The tendency to use older donors has gradually increased in the past 10 years. Donors over 50 years of age comprised 5% of the donors in 1978 and rose to 10% by 1987. 5. Transfusions, HLA-B,DR mismatches, and causes of failure were not related to donor age. 6. In transplants performed in the last 10 years, donor age did not play a significant role in either patient or graft survival. Whether or not this will hold true for more recent CsA-treated transplants remains to be seen. Recipient age. 1. The most significant effect of recipient age for patients transplanted since 1983 was on patient survival: it dropped from 100% for 6- to 7-year-old recipients to 86% for 68- to 71-year olds. 2. There is an increased tendency to transplant patients older than 50. The number rose from 14% in 1978 to 25% in 1987. 3. A very strong association was noted between advancing recipient age and corresponding decrease in immunologic failures and increase in nonimmunologic failures. Immunologic responsiveness to allografts decreased with age, though failures from nonimmunologic causes increased with age. 4. Patients with no transfusions had increasingly higher graft survival with age: 63% 1-year graft survival for patients up to 20 years old and 73% for those over 50 which was consistent with the above findings. Transfusions led to 1-year graft survival of about 76% in all groups. Thus, transfusions had less effect in older recipients.(ABSTRACT TRUNCATED AT 400 WORDS)

Eighteen patients were treated with primary cadaveric renal transplantation using cyclosporin A therapy, and four more patients undersent cadaveric retransplantation. Eleven of the 22 recipients were conditioned with lymphoid depletion before transplantation, using thoracic duct drainage or lymphapheresis for two to eight and one-half weeks. Cyclosporin A was begun a few hours before grafting. The other 11 patients were pretreated with cyclosporin A for from one day to 18 days. After transplantation, the majority of patients in both subgroups of 11 had rejection develop, but in most, the immunologic process was readily controlled with relatively small dosages of prednisone. After follow-up periods of two to four and one-half months, one patient has died of the complications of a coronary artery reconstruction that was not related to the transplantation. Another graft was lost from rejection, and a third organ was removed because of ureteral necrosis. Nineteen of the original 22 cadaveric kidneys are functioning, including 17 of the 18 kidneys given to patients who were undergoing transplantation for the first time. The only loss in the latter group of 18 patients was in the patient who died after an open heart operation. Results of these studies have shown that cyclosporin A is a superior and safe immunosuppressive drug but that, for optimal use in cadaveric transplantation, it usually should not be given alone. Steroid therapy greatly amplified the value of cyclosporin A. Unless major delayed morbidity develops which is not obvious so far, this drug combination should permit revolutionary advances in the transplantation of all organs. Other adjuncts to the cyclosporin A-steroid combination, including lymphoid depletion techniques, will require further investigation.

In Pima Indians with Type 2 (insulin independent) diabetes mellitus, HLA-A2 allele frequencies were inversely associated with age, (0.72, 0.59, and 0.52 in those less than 35, 35 to 54, and 55 years old and over, respectively). This suggests that there may be a gene closely linked with the HLA-A locus which plays a role in the expression of diabetes in the Pimas by contributing to an earlier age of onset. HLA-A2 was found in 65% non-diabetic and 81% of 191 diabetic subjects (relative risk = 2.2).

A monoclonal mouse antibody has been raised to the common acute lymphoblastic leukemia (cALL) cell line Reh. It is a cytotoxic antibody of the IgG2, subclass that reacts with leukemia cells from the following patients: 69% non-B non-T ALL, 50% T-ALL, 18% acute myeloblastic leukemia (AML), and 66% chronic myeloid leukemia (CML) blast crisis lymphoid cells. Other types of leukemia and all normal blood cells tested were negative, including T and B lymphocytes, granulocytes, monocytes, erythrocytes, and spleen cells. The detected antigen appears to be a type of blast cell antigen because it is also present on phytohemagglutinin (PHA) blast cells, myeloblast from normal bone marrow cells (by CFU-C), and all lymphoblastoid cell lines tested. Only one active antibody species could be detected by preparative isoelectric focusing on polyacrylamide gels and by protein-A-Sepharose affinity chromatography.

1. One-year patient survival rates improved markedly year by year for regrafted kidney patients reaching 93% in 1986, as compared with 96% in first grafts. 2. The graft survival rate of regrafts also showed steady improvement, but was not benefited by the introduction of CsA as much as in first grafts. One-year graft survival rate was 63% for regrafts in 1986. 3. The functional graft survival was higher with advancing recipient age in first grafts, but remained essentially constant regardless of age in regrafts. We interpret this to mean that older patients have depressed immunologic capability to reject first grafts, but those immunized patients by rejecting a first graft have undiminished reactivity. 4. A high graft survival rate of 68% at one-year was observed for patients who had been sensitized before their first transplant but lost their antibodies before the second transplant. One-year graft survival of those who were not sensitized before both first and second grafts was 60%. 5. The duration of first grafts significantly influences the outcome of second grafts (p less than 0.00001). The highest graft survival was obtained in recipients who had functioning first grafts for more than 2 years (69% at one year), followed by those for recipients whose grafts had functioned for one to 2 years, 6-12 months, and 3-6 months. Patients who lost their first grafts within 3 months had the lowest graft survival rate (44% at one year). 6. The time interval had an influence on the outcome of second grafts.(ABSTRACT TRUNCATED AT 250 WORDS)

1. In transplants performed between 1971 and 1986, first cadaver donor grafts had a half-life ranging from 6.6 to 7.5 years in the period after the first year. Second cadaver donor grafts had a half-life of 5.1 to 6.5 years. Parental donor grafts had a half-life of 9.3 to 11.8 years, whereas HLA identical sibling donor transplants had a half-life of 19.1 to 26.5 years. Siblings with no haplotype in common had an average half-life of 8.7 years. 2. Between 1971 and 1984, white recipients had an average half-life of 7.7 years, which increased to 9.3 years in 1985-1986. Black recipients' half-life decreased from 5.4 years in 1975-1976 to 3.5 years in 1985-1986. The reason for this decrease is not apparent. 3. The half-life of transplants of different recipient ages did not vary significantly. The average half-life during this period of study was 7.4 years for those younger than 21 years of age, 8.2 years for recipients 21 to 50 and 6.7 years for those older than 50. 4. In the early data, there was some evidence that the half-life of kidneys with cold ischemia below 13 hours was superior. However, in the latest period (between 1983 and 1986) the average half-life was 7.6 years for CIT below 13 hours, 7.2 years for those with 13 to 24 hours and 6.4 years for more than 24 hours. 5. For patients receiving kidneys with no HLA-A,B mismatches, the average half-life was 10.1 years. Those with A,B mismatches had a half-life of 6.7 years, and for those with no A,B antigens in common, the average half-life was 6 years. 6. In the period after 1981, the average half-life of patients with no A,B,DR mismatches was 9.1 years compared with 6.5 years for those with A,B,DR mismatches and 5.4 years for those with no A,B,DR antigens in common.

The majority of human lymphocytic and myelocytic leukemia cells express a polymorphic antigen that is found on peripheral blood B-lymphocytes and cultured lymphoblastoid B-cell lines. These B-lymphocyte antigens were detected by 34 human alloantisera that were repeatedly absorbed with pooled platelets to remove all activity against HLA antigens and T-lymphocytes. Absorption studies indicated that a common antigen was present on both B-lymphocytes and positive leukemia cells. Leukemia cells could be subdivided into two groups based on the presence of the B-lymphocyte antigen. Fourteen of 18 acute myelocytic leukemia cells, 10 of 13 acute lymphoblastic leukemia cells, 4 of 6 chronic myelocytic leukemia cells, and 2 of 2 chronic lymphocytic leukemia cells were positive. This group of leukemia cells also reacted with rabbit anti-B-cell sera raised to papain digests of spleen cell membranes. F(ab')2 fragments of the rabbit antsera were shown to specifically block the reactions of the human antisera against B-cells and leukemia cells. These results suggested that the rabbit and human anti-B-cell sera were reacting with identical molecules. This conclusion was supported by immunoprecipitation data.

1. Among patients transplanted in 93 selected centers with good follow-up data, the 10-year graft survival of first cadaver-donor transplants was 18%, parental donor grafts 39%, and HLA-identical sibling donor grafts 66%. The respective half-lives were 6.8, 10.8, and 24.5 years. The donor relationship has been the most important factor in long-term success. 2. Patient half-life for recipients younger than 16 was 36 years; for recipients 16-50 years old it was 17.6 years, and for those over age 50, it was 10.4 years. This marked difference in patient half-lives severely affected functional graft half-lives for the 3 age groups; 6.8, 10.3, and 16.7 years, respectively. However, the differences in patient survival for the 3 age groups were not significantly reflected in graft half-lives that were 6.8, 7.7, and 6.5 years, respectively. Thus, graft loss resulting from rejection was significantly lower in older than in younger patients. 3. Cadaver-donor kidneys with cold ischemia time up to 12 hours and half-lives of 9.1 years in transplants performed before 1975, compared to half-lives of 6.4 years for those with more than 24 hours cold ischemia time. In transplants performed between 1980 and 1983, the half-life of kidneys with cold ischemia time up to 12 hours was 8.7 years, compared to 6.9 years for those with more than 24 hours cold ischemia time. The long-term effect of cold ischemia persists but has diminished in recent years. 4. HLA-A,B loci matching had a significant effect on long-term graft survival. The 10-year graft survival of A,B matched grafts was 30% compared to 18% for 3 or 4 HLA-A,B mismatched transplants. This difference increased at 15 years to 25% in the matched grafts and 10% in the mismatched grafts. 5. A very strong recipient race effect was evidenced by the 24% 10-year graft survival in Whites compared to 10% in Blacks. The half-lives were 8.2 in Whites and 4.8 in Blacks. 6. A listing of 15-year graft survivors has been compiled according to transplantation centers. There was a total of 969 from cadaver donors, 283 from parental donors, and 457 from sibling donors. 7. An analysis of the characteristics of the 15-year graft survivors showed a preponderance of patients with favorable factors, noted in the analysis above. As might be expected, the most striking was the fact that 27% of the 15-year survivors had received kidneys from sibling donors, despite the fact that such donors comprised only 17% of those transplanted in the pre-1975 era.