Search

Background: Pediatric kidney graft survival rates have improved in the United States. This study evaluates early and late risk factors for cadaveric graft loss in pediatric recipients., Methods: From January 1994 to December 2002, 2,597 primary cadaveric kidney-alone transplants (donor age 5-45 years, recipient age 2-20 years) were reported to the United Network for Organ Sharing (UNOS). The analysis includes follow-up information based on OPTN data as of October 14, 2003. Odds ratio of early graft loss and relative risk of late graft loss are estimated using logistic regression and Cox proportional hazards model, respectively., Results: Graft survival rates significantly improved during 1999-2002 (95% and 79% at 1-year and 3-years, respectively) compared with those of 1994-1998 (88% and 76% at 1-year and 3-years, respectively) (log rank P=0.02). After adjusting for other variables, the factors that significantly affected early transplant outcome adversely within 3 months posttransplant were prolonged cold ischemia time (>36 hours, odds ratio [OR]=3.38 vs. 0-36 hours) and young recipient age (2-5 years old, OR=2.02 vs. 6-12 years). Beyond 3 months, significant risk factors were African-American recipients (relative risk [RR]=1.93 vs. others), teenage recipients (13-20 yrs, RR=1.50 vs. 6-12 yrs), and patients with focal glomerulosclerosis (FGS) (RR=1.27 vs. others)., Conclusions: The short-term graft survival rate of pediatric cadaveric kidney transplants has significantly improved, yet the long-term outcome has changed little. The long-term outcomes for teenagers (13-20 yrs), patients with FGS, and African-Americans lag significantly behind other groups. In order to improve long-term graft survival in these high-risk patients, newer preventive or treatment strategies must be developed.

Control serum levels of IL-6 measured by ELISA in 30 healthy blood donors or volunteers were 18 +/- 34 pg/ml (mean +/- SD). Pretransplant serum levels of IL-6 in 169 adult candidates for liver transplantation were significantly higher than control in those with fulminant hepatitis (203 +/- 232 pg/ml), alcoholic cirrhosis (116 +/- 257 pg/ml), and hepatocellular carcinoma (82 +/- 105 pg/ml). With these data as background, plasma or serum levels of IL-6 were monitored in 24 adult patients after first OLT and correlated with the clinical courses and the histopathological diagnosis of rejection. Serum or plasma levels of IL-6 decreased after transplantation regardless of pretransplant value. Four patients with infection subsequently developed continuously high IL-6 values. In the 20 of 24 patients who did not have infection, significantly higher levels of IL-6 were consistently found 0-4 days before histopathological diagnosis of rejection (131 +/- 78 pg/ml) compared with significantly lower values in patients without rejection episodes (40 +/- 21 pg/ml). The elevations of IL-6 were spike shaped, did not correlate well with the histopathological grades of rejection, and were highly responsive to augmented immunosuppression. These 20 cases were classified as: group 1, no spikes of IL-6 after liver transplantation; group 2, single spike of IL-6 after liver transplantation; and group 3, multiple spikes of IL-6 after liver transplantation. The combined early and late graft loss of each group was 0% (group 1), 25% (group 2), and 67% (group 3). We conclude that daily monitored serum or plasma IL-6 levels can be a good premonitor of liver allograft rejection and also a useful predictor of long-term graft outcome.

Second clinical kidney grafts often survive longer than first grafts. Using a rat cardiac allograft model, we examined the conditions under which survival of a second graft can be longer than first graft survival. In the BUF-to-LEW combination, following rejection of the first transplant, second cardiac allografts from the same donor strain implanted immediately survived longer than the first grafts (P = 0.047). Although the mean survival time of first grafts was 9.0 days, second grafts implanted in the same animals survived 19.5 days. In contrast, when ACI donors were used for the same LEW recipients, the second grafts were rejected in 3 days compared with 6.6 days for first grafts. Donor-specific spleen cell transfusions in these combinations resulted in prolonged survival in the BUF to LEW combination, but had no effect when the donor strain was ACI. Second grafts from BUF had prolonged survival following rejection of the first graft. Thus the histocompatibility difference was a determining factor of whether or not prolongation would be obtained. Another factor was timing of the second transplant. If 7 days were allowed to elapse following rejection of the first graft before implantation of the second, the enhancement effect was lost. Moreover, in the LEW-to-ACI combination in which second grafts were rejected rapidly, removal of the first graft after 7 days (before rejection), resulted in prolonged survival of the second graft. There is, therefore, a window of time before rejection of first grafts and shortly thereafter, when the enhancement effect can be obtained. Passive transfer of serum in the BUF-to-LEW combination resulted in enhancement, but transfer of splenic cells was ineffective. We conclude that graft rejection can result in induction of enhancement during a specific period, after which this effect is lost; and that enhancement can be obtained only in certain strain combinations. This suggests that human patients with heart transplants that reject might benefit from a second graft, even from a donor with a mismatch similar to the first graft.

Because of the liver graft's ability to resist cytotoxic antibody-mediated rejection, it has become dogma that the conventional transplant crossmatch used to avoid hyperacute rejection of other organs is irrelevant to the liver. We examined this hypothesis in a consecutive series of adult primary liver recipients treated with FK506 and low-dose steroids. Twenty-five of 231 (10.8%) patients received a liver from a cytotoxic-positive crossmatch donor (more than 50% of donor T lymphocytes were killed by dithiothreitol-pretreated recipient serum). The outcome was compared with that of 50 negative crossmatch patients who had their transplantations just before and after the crossmatch positive cases. The one-year graft and patient survivals were 56% and 68%, for positive and 82% and 86% for negative crossmatch patients (P = 0.004, P = 0.03, respectively). The difference between patient and first graft survival was accounted for by retransplantation, which was 4 times more frequent in the positive-crossmatch cases. Histologically, failed allografts obtained at the time of retransplantation revealed a spectrum of pathologic findings related to vascular injury. This study showed a higher difficulty of intraoperative blood product management, a degraded prognosis, and a poorer average quality of ultimate graft function when liver transplantation was performed against positive cytotoxic crossmatches. In such patients for whom crossmatch-negative donors may never be found because of the broad extent and intensity of sensitization, special therapeutic strategies perioperatively must be evolved if results are to improve.

A multiscreen serum analysis program has been developed that permits a determination of antibody specificity for the vast majority of highly sensitized patients awaiting transplantation. This program is based on a 2 x 2 table analysis of correlations between serum reactivity with an HLA-typed cell panel and incorporates two modifications. One implements the concept of public HLA determinants based on the serologic crossreactivity among class I HLA antigens. The other modification derives from the premise that most highly sensitized patients maintain the same PRA and antibody profiles over many months and even years. Monthly screening results for patients with persistent PRA values can therefore be combined for analysis. For 132 of 150 highly sensitized patients with greater than 50% PRA, this multiscreen serum analysis program yielded information about antibody specificity toward public and private class I HLA determinants. The vast majority of patients (108 of 112) with PRA values between 50 and 89% showed antibody specificity generally toward one, two, or three public markers and/or the more common private HLA-A,B antigens. For 24 of 38 patients with greater than 90% PRA, it was possible to define one or few HLA-specific antibodies. The primary objective of the multiscreen program was to develop an algorithm about computer-predicted acceptable and unacceptable donor HLA-A,B antigens for patients with preformed antibodies. A retrospective analysis of kidney transplants into 89 highly sensitized patients has demonstrated that allografts with unacceptable HLA-A,B mismatches had significantly lower actuarial survival rates than those with acceptable mismatches (P = 0.01). This was shown for both groups of 32 primary transplants (44% vs. 67% after 1 year) and 60 retransplants (50% vs. 68%). Also, serum creatinine levels were significantly higher in patients with unacceptable class I mismatches (3.0 vs. 8.4 mg% [P = 0.007] after 2 weeks; 3.9 vs. 9.1 mg% [P = 0.014] after 4 weeks). Histopathologic analysis of allograft tissue specimens from 47 transplant recipients revealed a significantly higher incidence of humoral rejection (P = 0.02), but not cellular rejection, in the unacceptable mismatch group. These results suggest that the multiscreen program can establish which donor HLA-A,B mismatches must be avoided in kidney transplantation for most highly sensitized patients. For 18 of 150 high PRA renal dialysis patients, the multiscreen program could not define HLA-specific antibody. Most patients had greater than 90% PRA, and many of their sera appeared to contain IgM type nonspecific lymphocytotoxins that could be inactivated by dithioerythreitol (DTE).(ABSTRACT TRUNCATED AT 400 WORDS)

Plasma levels of tumor necrosis factor-alpha were measured in 50 adult patients following orthotopic liver transplantation. The mean (+/- SEM) plasma concentration of TNF-alpha was significantly higher in patients experiencing a rejection episode (941 +/- 83 pg/ml) than in those with a stable clinical course (240 +/- 6 pg/ml; P = 0.0001). Peak levels of TNF-alpha were usually found at the time of clinically diagnosed rejection, although elevated levels were observed 1-2 days earlier. First-week peak TNF-alpha levels were significantly higher in patients who suffered graft loss (2146 +/- 788 pg/ml) than in those who were discharged from the hospital without clinical evidence of rejection (581 +/- 93 pg/ml; P = 0.004). TNF-alpha levels were not correlated with white blood cell count (r2 = 0.004), cyclosporine levels (0.01), serum creatinine (0.002), serum bilirubin (0.05), serum SGOT (0.03), or SGPT (0.05). TNF-alpha levels were not elevated in four cases of viral hepatitis occurring after transplantation. We conclude that circulating levels of TNF-alpha are elevated during liver allograft rejection and may precede clinical manifestations. First-week TNF-alpha levels are also useful predictors of long-term graft outcome. Further investigation is required to determine whether this monokine is important in the actual pathogenesis of allograft rejection.

The transfusion effect in first cadaver kidney transplants was re-examined at the UCLA Transplant Registry. One-year graft survival rates were 71% for non-transfused patients, which improved to 75% (P less than 0.05) with a single transfusion, 77% (P less than 0.01) with 2, and 78% (P less than 0.01) with 3 and 4 transfusions. One-year graft survival rates did not improve further with additional transfusions but remained at the same level. Thus, the transfusion effect clearly does exist, and 2 to 4 transfusions are sufficient to obtain the maximum beneficial transfusion effect. Patients with zero HLA-DR mismatched transplants had no blood transfusion effect. Transfusions improved the 1-year graft survival rate by 8% for transplant recipients with 1 DR-mismatched grafts (P less than 0.01) and by 10% with 2 DR-mismatched grafts (P less than 0.01). The transfusion effect was greater in Black than White recipients; however, the 77% 1-year graft survival rate for transfused Black recipients of zero DR-mismatched kidneys did not differ from that of transfused comparably matched Whites. We conclude that transfusion protocols should not be abandoned unless patients receive zero DR-mismatched kidneys.

The data of the UCLA Kidney Transplant Registry were reviewed with regard to sharing. The percentage of first-cadaver cyclosporine-treated transplants since 1984 with long cold ischemia time increased with sharing distance: 25% of unshared grafts, 40% of locally shared, and 61% of distantly shared ones had cold ischemia times over 24 hr; for cold ischemia times over 36 hr the numbers were 6%, 12%, and 24%, respectively. The immediate function rate did not parallel sharing distance the way cold ischemia time did: 85.7% without sharing, 74.4% with local sharing, and 83.5% with distant sharing. The percentage of well-matched (0 HLA-B,DR mismatches) transplants was low (3-5%) regardless of sharing status. Well-matched shared grafts with cyclosporine immunosuppression had a 9% survival advantage at one year compared with poorly matched unshared ones (85% vs. 76%). Long-term, well-matched shared grafts had a half-life of 11.9 years compared with 7.5 years for poorly matched unshared ones (reflecting graft loss from 3 to 10 years posttransplant). We conclude that sharing for histocompatibility has an overall beneficial effect.

When the pretransplant sera of cadaver donor transplant patients were divided into 132 with anti-F(ab')2 (Fab) antibodies and 121 without anti-Fab antibodies, those patients with the antibodies had a 2-year graft survival rate of 59.7 +/- 4.6% (+/- SE) as compared with 34.0 +/- 5.0 % (+/- SE) for those without antibodies (P less than 0.001). This difference was greater when the patients were further classified by whether they had antibodies reactive to B lymphocytes in the cold. Patients with anti-Fab antibodies and B-cold antibodies had a 2-year graft survival of 81.3 +/- 9.8% as compared with 15.7 +/- 7.9% for patients without anti-Fab antibodies and with B-cold antibodies. We suggest that these anti-immunoglobulin antibodies may function in some immunoregulatory role. The number of transfusions was not directly related to the frequency of occurrence of these antibodies.

To test the clonal deletion hypothesis, different levels of immunization were carried out by 0, 1, 2, or 3 transfusions preoperatively, together with 10 methods of immunosuppression. In this way, it was hoped that we could determine the optimal way to immunize and the optimal immunosuppressant treatment to deactivate the responding cells. With the Buffalo-to-Lewis rat heart allograft model, the control mean survival rate was 7 days. Rats with 2 or 3 transfusions had 5- and 12-day survival rates, respectively. If azathioprine was given in addition before grafting, 19- and 18-day survival rates were seen, and if azathioprine was given after grafting, extended survivals of 33 and 34 days were achieved. The longest survival rate of greater than 52 days was obtained by a single transfusion and 25 mg/kg/day of cyclophosphamide given before transplantation. Splenectomy following 2 or 3 transfusions prolonged survival rates to 16-18 days, suggesting that mechanical removal of immunized cells is somewhat effective. Most of the antibody produced by one transfusion was IgM, as were antibodies that resulted from transfusions followed by azathioprine. It is possible that reduction of IgG-producing cells is important. These results are consistent with the clonal deletion theory, although they do not necessarily provide final proof. The experiments suggest that the optimal transfusion effect may be obtained with minimal immunization (1 transfusion) and proper immunosuppression before transplantation.

Over 200 cadaver donor transplants were crossmatched against T and B lymphocytes at 5 and 37 C. Of 54 positive B cell crossmatches, one-half had cold antibodies and one-half had warm antibodies. The 1-year transplant survival was 58% for B-cold-positive crossmatches and 42% for B-warm-positive crossmatches. The B-warm-positive crossmatches, when subdivided into those with strong HLA-DR antibodies showed a 27% 1-year transplant survival rate. We conclude that B cell-positive crossmatches with HLA-DR antibodies are deleterious and that those with cold anti-IgM antibodies may enhance graft survival.

A mouse monoclonal antibody (CIA) produced against human Ia antigens that reacts with 20-30% of human peripheral blood lymphocytes was found to react with more than 90% of dog lymphocytes. Less than 41% of the Ia-positive dog lymphocytes expressed surface immunoglobulins. Immunoprecipitation studies with 125I-labeled cells precipitated heavily labeled Ia bands at 28K and 35K from human cells, but from dog cells the 29K beta chain of Ia was much more heavily labeled than the alpha chain.

An immuno-reduction-suppression protocol using spleen cell infusion followed by cyclophosphamide (CP) or azathioprine (AZ) to reduce the immunocompetent cells and maintenance suppression with low-dose cyclosporine (CsA) was highly effective in a rat cardiac transplant model. Following one or two spleen cell infusions, AZ or CP treatment was given before transplantation. After transplantation the animals were maintained with low-dose CsA. Among those treated with AZ, five of eight survived greater than 100 days, and among those treated with CP, six of eight survived greater than 100. These two protocols were far superior to 28 other permutations of treatment consisting of 164 transplants, such as infusions plus AZ without CsA and infusions without AZ but with CsA. We conclude that CsA can most effectively be used in low dose as a maintenance drug and that immunoreduction therapy is optimized by prestimulation and expansion of reactive cells. Another important feature of this proposal is that the immunoreductive risk phase, performed before transplantation, can be separated from the operative risk period. This avoids the conventional superimposition of the two risks.