Occurrence Of Acute Rejection Research Articles

Cadaveric full-size liver transplantation and the graft alternatives in adults: A comparative study from a single centre

This study aims to compare the results of living donor (LDLT), cadaveric split (SLT) and domino (DO) liver transplantation which are currently available alternatives to the conventional cadaveric full-size liver transplantation (CAD). Immunologic, vascular and biliary complications (BC) were evaluated in 38 LDLT, 20 SLT, 17 DO and 38 CAD recipients. The incidence of acute rejection (AR) was similar between groups, and between blood-related and blood-unrelated patients. AR was more severe in the SLT group according to the Banff scores (P=0.03, P<0.001, P<0.001). The evolution of AR was similar between the groups, in terms of development of chronic rejection. No venous complications occurred in the overall population. The rate of arterial thrombosis (10.5, 10, 0 and 3%, respectively) was statistically similar between groups. The rate of BC (26, 40, 12, and 8%, respectively) was higher in the partial grafts than in the whole grafts (P=0.006), but was not significantly different within each group. There was an association between the severity of preservation injury and occurrence of AR (P=0.01) and arterial thrombosis (P=0.016), but not BC. One- and 2-year graft and patient survival rates were similar between groups. None of the graft types seemed to confer immunological advantage. BC remained problematic in the partial grafts, independently from ischemia time.

The Influence of Mycophenolate Mofetil Versus Azathioprine and Mycophenolic Acid Pharmacokinetics on the Incidence of Acute Rejection and Infectious Complications After Renal Transplantation

Purpose The present retrospective study investigated the influence of mycophenolate mofetil (MMF) instead of azathioprine (AZA) as part of tacrolimus-based immunosuppression. Mycophenolic acid (MPA) pharmacokinetic (PK) parameters were used for associations with the incidence of acute rejection (AR) episodes and infectious complications after renal transplantation. Methods The 66 consecutive renal transplant recipients reported herein excluded ABO-incompatible transplants or cytomegalovirus (CMV)-seronegative recipients. The immunosuppressive regimen consisted of tacrolimus, steroids, and AZA 1–2 mg/kg/d in 22 patients (between February 1998 and December 2000) or MMF 2 g/d in 44 patients (since January 2001). CMV infection was defined as positive CMV-antigenemia. MPA PK was studied on day 28 after transplantation in 21 recipients. Results AR occurred in 13.6% of patients in the MMF group compared with 18.2% in the AZA group. The viral infection (CMV, varicella zoster virus, adenovirus hemorrhagic cystitis, and malignancy related to Epstein-Barr [EB] virus) rate was 22.7% in the MMF group and 0% in the AZA group ( P = .015). There were no bacterial or fungal infections observed in the 2 groups. MMF dose per body weight was significantly lower among patients with AR than those without AR (25.1 vs 35.6 mg/kg; P = .026). There were no differences in MPA PK parameters between patients with and without viral infections. Conclusions Patients treated with MMF required less treatment for AR, however, there were no significant differences. MMF dose per body weight may play an important role in the occurrence of AR. Although virus infections occurred in recipients treated with MMF, MPA PK did not influence the infectious complications after renal transplantation.

1619: The Nighttime Mycophenolic Acid Area Under the Curve Influences the Occurrence of Acute Rejection in the Early Stage in Renal Transplant Recipients

1619: The Nighttime Mycophenolic Acid Area Under the Curve Influences the Occurrence of Acute Rejection in the Early Stage in Renal Transplant Recipients

Weight Gain After Living-Related Renal Transplantation Affects Long-Term Graft Function

Weight gain is a common problem in renal transplant recipients. This study investigated whether weight gain after living-related renal transplantation affects long-term graft function. The cohort included 93 patients (28 females, 65 males of mean age, 33.78 ± 9.78 years who were recipients of kidneys from living-related donors. The data set related risk factors to occurrence of chronic allograft nephropathy (CAN): namely, number of HLA mismatches, PRA levels, delayed graft function, acute rejection, suboptimal immunosuppression, hypertension, hyperlipidemia, and size mismatch. Patients with a 10% increase in body mass index sustained throughout at least 2 years posttransplantation were categorized as group 1 (abnormal weight gain; n = 65) and the others were categorized as group 2 (no or normal weight gain; n = 28). Chronic allograft nephropathy was more frequent among group 1 ( P < .03). The mean times to CAN diagnosis in groups 1 and 2 were 1053.41 ± 461.86 days and 1128.57 ± 416.09 days, respectively ( P > .05). Of all the risk factors for CAN, occurrence of acute rejection was the most important (OR = 5.39, 95% CI: 2.07 to 14.03, P < .001). When this factor was excluded, weight gain emerged as the most important risk factor (OR = 3.04, 95% CI: 1.01 to 9.69, P < .04). There were no significant differences between the groups with respect to the frequencies of immunologic and nonimmunologic risk factors ( P > .05 for all). The results suggest that excessive weight gain after living-related renal transplantation may be an additional risk factor for development of CAN. Patients should pay attention to diet and control weight gain after transplantation.

Basic concepts in transplant immunology

Subsequently,spontaneousliverallograftacceptancewasalsoobservedintransplants done in several allogeneic rat strain combina-tions and most allogeneic mouse strain combinations.Moreover, other experimental studies in rodents demon-strated that allogeneic liver transplantation providesimmune“protection”againstsubsequentcardiac,kidney,pancreas, islet, and skin grafts from the same donor.

Cytokine gene polymorphisms and acute liver graft rejection: A meta-analysis

In the field of liver transplantation, 7 reports have been published investigating the association between polymorphisms in cytokine genes and the occurrence of acute rejection in liver graft recipients. However, most of the individual studies lack the statistical power to detect a small-to-moderate effect of cytokine gene polymorphisms on the acute rejection rate. To overcome this problem, we performed a quantitative meta-analysis of 7 gene-association studies that were comparable with regard to definition of acute rejection and the type of immunosuppression used. In the overall analysis, the interleukin (IL)-10 polymorphism at position -1082 was identified as a genetic risk factor for acute liver graft rejection; liver transplant recipients carrying the IL-10 -1082.A allele displayed a lower rejection rate (common odds ratio [OR], .6; 95% confidence interval [CI], .4-.9). For the tumor necrosis factor (TNF)-A -308 polymorphism, a common OR could not be calculated due to significant heterogeneity of ORs between the studies (mean OR, 1.4; 95% CI, .8-2.6). No associations were found between acute liver graft rejection and single nucleotide polymorphisms in the IL-6 (position -174) and transforming growth factor (TGF)-beta1 (positions +869 and +915) genes. In conclusion, results from this meta-analysis suggest a role for the IL-10 -1082 polymorphism in human liver graft rejection.

Early Adequate Mycophenolic Acid Exposure is Associated with Less Rejection in Kidney Transplantation

This study examines the importance of early mycophenolic acid (MPA) exposure in the cyclosporine- and mycophenolate mofetil (MMF)-treated kidney transplant population.We prospectively evaluated 94 first solitary kidney transplant patients treated with cyclosporine (Neoral), MMF, and prednisone. Basiliximab was also given to 72 recipients. MPA exposure was measured by HPLC using a limited sampling estimate of 12 h area under the curve (AUC [0–12]) within the first week. Efficacy was determined by the occurrence of acute rejection and toxicity by the need to reduce MMF doses within the first 3 months post-transplantation.Acute rejection was observed in 14 (15%) and MMF toxicity in 27 (29%). Receiver operator curve analysis shows that MPA AUC [0–12] on day 3 was predictive of efficacy (c = 0.72, p = 0.007) but not toxicity (c = 0.57, p = 0.285). A separate analysis of only patients on basiliximab shows that the MPA AUC [0–12] on day 3 was also predictive of efficacy (c = 0.80, p = 0.01). Therefore early adequate exposure to MPA by day 3 is associated with low acute rejection but cannot predict toxicity. Adequate MPA exposure is also important with basiliximab induction therapy.

Study 1: characterization of acute rejection episodes after pre-emptive plasmapheresis and cytomegalovirus hyperimmune globulin to abrogate a positive crossmatch and allow live donor renal transplantation

P atients who undergo desensitization protocols to allow renal transplantation despite a positive crossmatch to their living donor remain at risk for acute rejection, specifically, antibody-mediated rejection. Our center uses plasmapheresis and cytomegalovirus hyperimmune globulin (PP-CMVIg) to precondition such patients. In this study, we seek to identify those patients at highest risk for antibodymediated rejection, allowing future modifications to decrease the incidence of acute rejection. All 33 patients treated with PP-CMVIg before live donor renal transplant (Feb 1998–Oct 2002) were analyzed. Episodes of acute rejection were confirmed by biopsy. Diagnostic criteria for antibody-mediated rejection included compatible histologic findings, positive C4d immunohistochemical results, and rising donor-specific antibody titer. Acute rejection occurred in 21 of 33 patients (64%), at a median of 9 days after transplantation, and 12 of 21 were diagnosed with antibody-mediated rejection. Antibody-mediated rejection was treated with steroids and additional PP-CMVIg treatments (mean, 4.3); steroids with or without antilymphocyte therapy were used to treat the 9 other cases of acute cellular rejection. Three patients sustained graft loss, as follows: 1 noncompliance, 1 hemolytic uremic syndrome, and 1 associated with patient death from surgical complications. Patients with an initially positive cytotoxic crossmatch (vs flow, P .007), a positive cytotoxic crossmatch at transplant (vs negative, P .032), and patients who required 6 pretransplant PP-CMVIg treatments (P 0.012) had a higher risk of acute rejection. Occurrence of acute rejection was associated with a longer length of stay (16 vs 5 days, P .0001) and lower 1-week creatinine clearance (43 vs 65 mL/min, P .01). Patients who had an episode of acute rejection had no significant change in their current creatinine clearance (75 vs 73 mL/min at 16 months’ mean follow-up, P .9). Patients with antibody-mediated rejection did not have significantly different outcomes compared with those with cellular rejection alone. Intensity of C4d and donor-specific antibody titer did not predict graft function. Donor-specific antibody remains undetectable in 28 of 30 patients with a functioning allograft. Conclusions: Patients receiving PP-CMVIg to abrogate a positive crossmatch are at risk for acute rejection, especially antibody-mediated rejection, but are responsive to additional PP-CMVIg. Acute rejection does not have an impact on graft function at 1 year. Patients with high levels of donor-specific antibody, as evidenced by an initially positive cytotoxic crossmatch, a positive cytotoxic crossmatch at the time of transplantation, and a requirement of more pretransplant PP-CMVIg treatments, are at highest risk for antibody-mediated rejection and require vigilant observation during the first 2 weeks after transplantation. From the Departments of Surgery, Medicine, and Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD. © 2003 Elsevier Inc. All rights reserved. 0955-470X/03/1704-0000$30.00/0 doi:10.1016/j.trre.2003.10.002

Ten-year survival of second kidney transplants: Impact of immunologic factors and renal function at 12 months

The aim of the present study was to assess long-term survival of cadaveric second kidney allografts performed in our center and to determine risk factors predictive of long-term graft outcome. Of 1704 kidney transplantations performed between January 1985 and March 1998, 233 were second grafts. The majority of the recipients were sensitized. All patients were treated with the same quadruple immunosuppressive regimen. Kaplan-Meier analysis documented graft survival of 89% at 1 year, 76% at 5 years, and 53% at 10 years. Graft survival was similar for second and primary kidney transplants performed during the same period of time. When long-term second graft survival was examined, only two risk factors were found to be significant: (1) the degree of human leukocyte antigen (HLA) DR mismatch (MM) and (2) the number of acute rejection episodes. Multivariate analysis of several pre- and posttransplant variables also confirmed the importance of HLA MM (DR> A), but also, identified serum creatinine at 12 months as the most significant predictor of graft survival. In addition, the Cox proportional hazards model revealed that only the year of transplantation had an independent significant effect on acute rejection occurrence (RR = 0.591, 95%CI 0.437 to 0.801, P < 0.0007). Indeed, the incidence of acute rejection was found to decrease over time (44% of patients experienced at least one episode of acute rejection before 1990 vs. 17% after 1990). Finally, second graft long-term outcome shows an improved evolution according to the time period resulting from a strong decrease in acute rejection incidence and the impact of creatinine at 12 months.

Early evolution of nutritional status and body composition after kidney transplantation

Background: Previous series have dealt with nutritional status after kidney transplantation. However, few studies have described the outcome of body composition after kidney transplantation. Methods: A total of 44 cadaver kidney transplant recipients (28 men and 16 women) were followed prospectively during the first post-transplant year. Biochemical nutritional markers, dietary records, anthropometric measurements, and body composition were assessed at kidney transplantation and 3, 6, and 12 months later. Results: By the end of the first year, serum albumin level was not significantly different from initial values. Prealbumin and retinol binding protein decreased from 42.3 ± 10.2 mg/dL to 30.4 ± 6.3 mg/dL and from 1.96 ± 0.61 g/dL to 0.65 ± 0.2 g/dL (P < 0.0001). Separating patients by gender showed that dietary caloric and protein intake increased in women only. At the end of the follow-up period, mean weight change was +5.4 kg in women (P = 0.009) and −0.9 kg in men (not significant). Body composition analyses showed that in women total fat and lean masses increased (+2.1 kg, P = 0.05, and +2.4 kg, P = 0.006), whereas in men total fat mass decreased (−1.4 kg, P = 0.04), and total lean mass tended to increase (+0.5 kg, not significant). Percentage change in total bone mass was +1.4% in women (not significant) and −2.1% in men (P = 0.05). In multivariate analyses, an independent impact of female gender on weight gain was observed, although increased fat mass was related only to energy intake. Increased total lean mass was related to low steroid doses and the absence of acute rejection and delayed graft function. Bone loss was related to male gender and high steroid doses. Conclusion: Changes in body composition during the first year after kidney transplantation are modulated by gender, energy intake, steroid doses, the occurrence of acute rejection, and delayed graft function. © 2002 by the National Kidney Foundation, Inc.

Psychiatric and Psychosocial Outcome of Orthotopic Liver Transplantation

Background: The study aimed to explore the prevalence of psychiatric disorders among orthotopic liver transplantation (OLT) recipients, and to investigate how psychiatric morbidity was linked to health-related quality of life (HRQOL). Methods: We recruited 75 patients who had undergone OLT a median of 3.8 years previously (range = 5–129 months). Psychiatric morbidity was assessed using the Structural Clinical Interview for the DSM-III-R. Psychometric observer-rating and self-rating scales were administered to evaluate cognitive functioning (SKT), depressive symptomatology (HAMD₁₇), posttraumatic stress symptoms (PTSS-10), social support (SSS), and HRQOL (SF-36 Health Status Questionnaire). Treatment characteristics were obtained from medical records. Results: 22.7% (n = 17) of our sample had a current or probable psychiatric diagnosis according to DSM-III-R: 2.7% full posttraumatic stress disorder (PTSD) (n = 2), 2.7% major depressive disorder (MDD) comorbid to full PTSD (n = 2), 1.3% MDD comorbid to partial PTSD (n = 1), and 16% partial PTSD (n = 12). Patients with PTSD symptoms demonstrated lower cognitive performance, higher severity of depressive symptoms and more unfavorable perception of social support. OLT-related PTSD symptomatology was associated with maximal decrements in HRQOL. The duration of intensive care treatment, the number of medical complications, and the occurrence of acute rejection were positively correlated with the risk of PTSD symptoms subsequent to OLT. Conclusion: OLT-related PTSD symptomatology impairing HRQOL is a complication for a subgroup of OLT recipients. Health-care providers should be aware of the possible presence of PTSD in OLT survivors.

Cytokine gene polymorphisms and acute human liver graft rejection.

Interindividual differences exist in the capacity to produce cytokines. It has been reported that levels of in vitro cytokine production measured after stimulated cell culture are associated with polymorphisms in cytokine genes. Moreover, a correlation between heart, kidney, liver, and lung graft rejection or survival with cytokine gene polymorphisms has been described. In the present study, we analyzed the association of gene polymorphisms in T helper subtype 1 (T(H)1-), T(H)2-, and regulatory-type cytokines with human liver allograft rejection. Patients who received a primary liver graft from 1992 onward and were seen at the transplant outpatient clinic since then were included on this study (n = 89). Patients were HLA typed routinely. Biopsy-proven acute rejection occurred in 41 of 89 patients. After informed consent, blood was collected and DNA was obtained. Using amplification-refractory mutation system polymerase chain reaction, the following cytokine gene polymorphisms were determined: IL-2+166, IL-2-330, IL-15+13689, IL-15-80, TNF-A-308, TNFd3, IFN-G+874 (T(H)1-type cytokines), IL-4+33, IL-4-590, IL-6-174, IL-10-592, IL-10-819, IL-10-1082, IL-13+2043, IL-13-1055 (T(H)2 type cytokines), TGF-B1+869, and TGF-B1+915 (regulatory-type cytokines). Univariate analysis showed that polymorphisms of IL-10-1082, TGF-B1+869, and HLA-DR6 were significantly related to liver graft rejection. Multiple logistic regression analysis was used to assess which variables remained significantly predictive of acute rejection. Multivariate analysis showed that TGF-B1+869 and HLA-DR6 were independently associated with the occurrence of acute rejection. These findings suggest a role for the regulatory-type cytokine transforming growth factor-beta1 in human liver graft rejection.

Cytomegalovirus infection and graft rejection in renal transplantation.

Cytomegalovirus (CMV) infection and CMV disease have been associated with acute and chronic graft rejection. The introduction of the sensitive CMV antigenemia pp65 assay for detection of CMV infection allowed us to study the time course of CMV infection and acute rejection and the long-term outcome in renal transplant recipients with and without a CMV risk constellation. Prospective single center study including 48 renal transplant recipients at risk for CMV infection (donor and/or recipient CMV seropositive) and a control group of 36 CMV seronegative recipients of CMV seronegative kidney donors. Evidence of CMV infection was monitored by the CMV antigenemia pp65 assay every 1 to 2 weeks and compared with the occurrence of acute rejection in the posttransplant period and graft function at 5 years. CMV infection developed in 83% (40/48) of patients of the CMV risk group within 4 months posttransplant. A total of 18 of patients experienced an acute rejection episode (control group 16/36; P=0.65). In 12/18 CMV infection followed rejection and in three patients antigenemia preceded the diagnosis of rejection. In three patients CMV antigenemia remained negative. Five-year follow up: Patient survival (44/48 vs. 31/36; P=0.48), graft survival (38/48 vs. 27/36; P=0.79), number of patients with at least one acute rejection episode: CMV risk group: 42.1%, control group 51% (P=0.46), serum creatinine: CMV risk group:130 +/- 66 micromol/iter, control group: 126 +/- 37 micromol/ liter (P=0.56), proteinuria: CMV risk group: 0.02 +/- 0.02 g/mmol creatinine, control group: 0.02 +/- 0.02 g/mmol creatinine (P=1.0). CMV infection within 4 months posttransplant, as defined by a positive antigenemia assay was not found to be a risk factor for acute graft rejection or chronic graft dysfunction at 5 years.

Elevated blood pressure predicts the risk of acute rejection in renal allograft recipients

Acute rejection (AR) is a strong predictor of renal allograft survival. Recent advances in immunosuppression have reduced considerably the incidence of AR. Still, approximately 25% of patients have AR early post-transplant, and the factors that predispose to AR have not been fully clarified. The study includes 1641 adults, recipients of first cadaveric (CAD, N = 1195) or living related renal grafts (LRD, N = 446), transplanted in one institution. The variables associated with the occurrence of AR during the first year post-transplant were identified. By univariate analyses, AR was associated with the following variables: younger (P < 0.001); heavier (P = 0.003); and African American recipients (P = 0.002); CAD transplants (P = 0.001); higher number of HLA mismatches (P = 0.001); delayed graft function (DGF, P = 0.001); higher levels of serum creatinine post-transplant (P = 0.003); and higher levels of systolic and/or diastolic blood pressure (BP) post-transplant (P < 0.001). Higher BP levels were also associated with earlier AR episodes (P < 0.0001). By multivariable analysis AR was significantly associated with recipient age, number of HLA mismatches, DGF, pre-PRA and systolic BP. Analysis of BP measured weekly post-transplant indicated that elevated BP levels, even three weeks prior to the AR episode, were significantly associated with AR. For every level of BP, the use of BP medications was associated with a lower incidence of AR (P < 0.0001). Furthermore, the use of calcium channel blockers was also associated with lower incidence of AR (P = 0.001). Of note, 81% of recipients whose BP increased after the transplant had AR. In contrast, 22% of patients whose BP declined post-transplant had AR. Elevated BP levels post-transplant identify patients at high risk of AR independently of graft function. Treatment of BP and reduction of BP levels appears to be associated with a decreased risk of AR. We hypothesize that high BP may be an indicator of a particular type of allograft damage, perhaps ischemic, that may predispose to AR.

A study of cytokine gene polymorphisms and protein secretion in renal transplantation

Although there is evidence that cytokine gene polymorphisms are associated with varying quantities of cytokine protein production, the exact role of these polymorphisms in allograft rejection remains unclear. In a previous study, we demonstrated a significant association between high IL-10 secretion in mixed lymphocyte culture (MLC), together with HLA mismatching for at least 4–6 antigens, with the occurrence of acute rejection following renal transplantation. We, therefore, wished to ascertain whether cytokine gene polymorphisms are associated with varying levels of protein secretion and/or allograft rejection in the same group of patients. Cytokine protein secretion in MLC for IL-4, IL-6, IL-10 and IFN-γ was measured by ELISA in 49 patient-donor pairs. Protein secretion for the above cytokines was also measured in phytohaemagglutinin (PHA) stimulated cultures in 30 normal controls. In both patient and control groups, single nucleotide polymorphism analysis for IL-4 G(−590)T, IL-6 G(−174)C, IL-10 G(−1082)A, IL-10 C(−819)T, IL-10 C(−592)A, TNF-α G(−308)A and microsatellite analysis for IFNG (CA repeat) was performed. No correlation was found between cytokine gene polymorphisms and cytokine protein secretion in either mitogen stimulated cultures (control group) or MLC (patient group). In addition, no correlation was demonstrated between cytokine gene polymorphisms and renal allograft rejection.

Acute rejection of hepatic allografts from HLA-DR13(Allele DRB1*1301)-positive donors

Acute rejection of hepatic allografts does not show consistent association with the number of mismatches of HLA classes I and II. Therefore, we investigated the relation between specific donor or recipient HLA antigens and the occurrence of acute rejection. HLA typing of 35 liver transplant recipients and donors was performed by serological standard technique, with confirmation and subtyping by polymerase chain reaction with sequence-specific primers. HLA class I antigens were not associated with the occurrence of acute rejection. The graft was positive for HLA-DR13 in 8 of 13 transplant recipients (62%) with acute rejection, but only 4 of 22 recipients (18%; P =.024; P(Bonferroni-corrected) =.33, not significant) without rejection. The graft was positive for DRB1*1301 in 7 of 13 recipients (54%) with acute rejection, but only 1 of 22 recipients (5%) without rejection (P =.002; P(Bonferroni-corrected )=.028). This patient had experienced long-lasting bacterial sepsis, which markedly reduced the risk for acute rejection. We speculate that the expression of donor DRB1*1301 (if mismatched) may increase the risk for acute hepatic allograft rejection.

The effect of polymorphisms in tumor necrosis factor-alpha, interleukin-10, and transforming growth factor-beta1 genes in acute hepatic allograft rejection.

The occurrence of acute rejection in orthotopic liver transplantation is unpredictable. The role of cytokines in the process of rejection is not entirely clear. We investigated polymorphisms in the genes encoding tumor necrosis factor (TNF)-alpha, interleukin (IL)-10, and transforming growth factor (TGF)-beta1, which affect the amount of cytokine produced in vitro, in a liver transplant population to determine any association with acute rejection. DNA was extracted from whole blood of liver transplant patients. After amplification with polymerase chain reactions, the polymorphisms at TNF-alpha -308, IL-10 -1082, and TGF-beta1 +869 and +915 were determined using sequence-specific oligonucleotide probes. Acute cellular rejection was a clinical and histological diagnosis. Acute cellular rejection requiring treatment occurred in 68 (48%) of 144 patients. Acute cellular rejection was significantly associated with the TNF-alpha -308 A/A genotype (P<0.02). There was no significant association with either IL-10 or TGF-beta1 polymorphisms in acute rejection. Patients with a homozygous TNF-alpha -308 genotype A/A are more likely to suffer from acute cellular rejection after liver transplantation.

Are donor-livers with low expression of CD80 at the time oftransplantation less susceptible to acute rejection?

ARE DONOR-LIVERS WITH LOW EXPRESSION OF CD80 AT THE TIME OF TRANSPLANTATION LESS SUSCEPTIBLE TO ACUTE REJECTION? J. Kwekkeboom, B. Bruyneel, H.W. Tilanus, J.N.M. Ijzermans, G.J. Bouma, P.E. Zondervan, H.J. Metselaar Liver Transplantation Research Group, Departments of Hepatogastroenterology, Surgery and Pathology, University Hospital Rotterdam, The Netherlands. We investigated the impact of per-operative expression of ¢o-stimulatory molecules in clinical liver-transplants on the occurrence of acute rejection. CD80 and CD86 expression were determined by immunohistochemistry on cryostate sections of three biopsies taken from each liver during transplantation: after the cold ischemie period, after the warm ischemic period and after reperfusion. CD86 was expressed in all livers on the majority of CD68+-Kupffer cells and in 12/15 livers on peri-vascular cells in the portal areas. CD80 was weakly expressed in the portal areas of only 6/15 livers. Expression of CDS0 on Kupffer cells was variable and appeared to be related to the occurrence of rejection. In 7/8 livers which were not rejected, CD80 was expressed on 0%-25% of the Kupffer cells. In 4/7 livers which were rejected CD80 was expressed on 50%-100% and in 2/7 on 25%,50% of the Kupffer cells. Since infiltrating T-cells in rejection-biopsies expressed abundant CD28 but nearly no CTLA-4, the CD80/CD86-signals delivered by the donor-liver will be stimulatory for the infiltrating T-cells. Conclusion: donor-livers with low CD80 expression on Kupffer cells at the time of transplantation seem to be less susceptible to acute rejection. Liver transplantation, surgery, acute liver failure

Risk factors for cancer in renal transplant recipients.

Cancer continues to be an important cause of morbidity and mortality after renal transplantation. Unfortunately, risk factors for cancer have not been well defined. We examined risk factors for invasive, life-threatening malignancies among 1500 renal transplant recipients. Both univariate and multivariate Cox proportional hazards analyses were used. There were 87 tumors in 88 patients. Actuarial survival free of cancer was 95.9% at 5 years, 92.3% at 10 years, 86.6% at 15 years, and 82.6% at 20 years. Among multiple possible risk factors, the adjusted, relative risk attributable to age at transplantation (compared to age <45 years) was 2.00 (95% confidence interval: 1.21-3.30, P = 0.007) for age > or =45 and <60 years (29.1% of total were in this age range), and 3.81 (95% confidence interval: 2.05-7.06, P<0.001) for age > or =60 years (11.6%). The relative risk attributable to pretransplant splenectomy (47.8%, now large abandoned) was 1.87 (95% confidence interval: 1.12-3.12, P = 0.016). Patients with renal disease from type 1 diabetes had a lower risk of cancer, 0.19 (95% confidence interval: 0.05-0.08, P = 0.015). A history of invasive cancer pretransplant (2.5%) increased the risk of posttransplant cancer to 2.38 (95% confidence interval: 1.18-4.83, P = 0.015). Cigarette smoking was also associated with an increased risk, with each 10 pack-years smoked at transplant increasing the risk of cancer by 1.12 (1.02-1.21, P = 0.016). The era when transplantation occurred, the type of prophylactic immunosuppression used, the occurrence of acute rejection, or its treatment did not alter the risk of cancer. The risk of cancer continues to increase 15-20 years after transplantation. The identification of splenectomy as a new risk factor, even several years after this immunosuppression strategy has been abandoned, demonstrates that the risk of immunosuppression may take years to become manifest. Efforts to reduce immunosuppression, particularly for patients > or =45 years of age at transplant, along with a greater effort to discourage cigarette smoking, may help reduce the risk of cancer after renal transplantation. cer in a cohort of patients with long-term follow-up. Although this is a retrospective study, the ongoing, continuous follow-up of these patients has made it possible to accurately assess the incidence of invasive malignancy.

DACLIZUMAB (ZENAPAX) IN PEDIATRIC (PED) RENAL TRANSPLANTATION AT UCLA.

701 Acute rejection (AR) precedes the development of chronic rejection and graft failure in up to 90% of ped renal transplant (Tx) patients (pts). Higher potency immunosuppressive (IMS) agents may be associated with higher rates of infectious complications and malignancy. Daclizumab (Dac) is a humanized monoclonal antibody with specificity for the α-subunit (CD25) of the IL-2 receptor (IL-2R) expressed on activated T cells. We retrospectively analyzed the data for 36 ped pts treated with Dac. Pts received Dac 1 mg/kg/dose IV within 24 hrs before Tx, and then biweekly for a total of 5 doses. Maintenance IMS consisted of triple therapy with cyclosporine (CsA), mycophenolate mofetil (MMF), and prednisone (PR) in all but one pt who received FK506 and prednisone. 14 pts (39%) received living related donor Tx. 33 were primary Tx and 3 were re-Tx. 4 pts (11%) were seronegative for CMV and received Tx from seropositive donors. Mean age was 13 yrs; 5 pts were 1-5 yrs, 8 were 6-12 yrs, and 23 were >12 yrs old. The mean follow-up was 484 days; 14 pts (39%) completed 1 yr, and 6 pts (17%) completed 6 months of follow-up. No first-dose or cytokine-release reactions were observed. No graft was lost to rejection, only one graft was lost immediately due to vascular thrombosis. Only 2 pts (5%) developed AR at days 67 and 41, both responded to solu-medrol. Infectious complications were infrequent: Bacteremia, peritonitis, and wound infection occurred each in 4 pts (11%), 8 pts (22%) developed urinary tract infections. Only 2 pts (5%) developed CMV viremia, both were seronegative for CMV and received Tx from seropositive donors. No pt developed EBV infection, post-Tx lymphoproliferative disease or other malignancy. IL-2R saturation studies with anti-CD25 and 7G7/B6 antibodies were available for the first 16 pts. IL-2R saturation was present after the first dose of Dac, and remained so for at least one month after the last dose. There was no increase in CD25 expression in the 2 pts who developed AR at the time of rejection. We conclude that the use of Dac in addition to the current triple therapy with CsA, PR, and MMF reduces the occurrence of AR without increasing the risk for adverse reactions or infections.