Pretransplant Transfusions Research Articles

Pretransplant Donor-Specific HLA Antibodies Detected by Single Antigen Bead Flow Cytometry: Risk Factors and Outcomes After Kidney Transplantation

BackgroundThe clinical significance of pretransplant donor-specific antibodies (pre-Tx DSAs) detected by single antigen bead flow cytometry (SAB-FC) remains unclear. Our aim was to investigate the impact that pre-Tx DSAs detected by SAB-FC have on the early and late clinical outcomes. Patients and methodsWe retrospectively tested stored frozen pre-Tx sera from 222 deceased-donor kidney transplants performed between November 1997 and November 2006. All patients had a negative complement-dependent cytotoxicity (CDC) cross-match with the donor. Median follow up was 5.1 years. ResultsTwenty-two (10%) patients had pre-Tx HLA antibodies detected by CDC. Pre-Tx HLA antibodies were detected using SAB-FC in the sera of 46 (20.7%) patients; 36 (16.2%) of them presented pre-Tx DSAs, 18 had class I antibodies, 9 class II, and 9 patients presented both classes. Mean pre-Tx DSA class I/II was 2360/1972 (MFI) mean fluorescence index in non CDC-sensitized patients. Pre-Tx DSAs were associated with female sex, retransplants, and pretransplant transfusions. Patients with Pre-Tx DSAs more than 1000 MFI and negative CDC screening presented a higher percentage of delayed graft function (61.1% versus 38.9%), more episodes of acute vascular rejection (33.3% versus 13.7%), and chronic rejection as the cause of allograft failure (22.2% versus 9.7%) compared with non-pre-Tx DSAs patients. Five-year allograft survival was significantly worse in patients with pre-Tx DSA (68.5% versus 82%, P = .006) and in patients with pre-Tx DSA class II more than 1000 MFI (43% versus 82%, P = .009). We didn't find differences in patient survival. DiscussionPre-Tx DSAs detected by SAB-FC were more frequent in female recipients, and they were associated with acute vascular and chronic rejection and a poorer graft outcome.

Audit of Peripheral Stem Cell Transplantation for Aplastic Anemia in Multitransfused Infected Patients

IntroductionAllogeneic hematopoietic stem cell transplantation is a curative modality for aplastic anemia; the preferred stem cell source is bone marrow. However, allogeneic peripheral blood stem cell transplantation (PBSCT) used in high-risk patients is associated with higher risk of chronic graft-versus-host disease (GVHD). Our center receives multitransfused, alloimmunized, infected, late referrals for transplant. MethodsForty-one patients of median age 22 years (range 8–37) received allogeneic-PBSCT from human leukocyte antigen (HLA)-matched sibling donors. The median time since diagnosis was 12 months (range 4–65) and median pretransplant transfusions were 37 (range 6–160). Six patients were platelet refractory and one alloimmunized for pan-red blood cell (RBC) antigens. Several patients had pretransplant icterus or renal dysfunction and 26 (63.4%) had unresponsive bacterial/fungal infections. Our conditioning regimen included fludarabine 30 mg/m2 for 6 days (days –10 to –5), cyclophosphamide 60 mg/kg/d for 2 days (days –6 to –5), and antithymocyte globulin (ATGAM) 30 mg/kg/d for 4 days (day –4 to –1), which was reduced to 2 days in 2 patients. We used standard GVHD prophylaxis with cyclosporine and methotrexate on days 1, 3, 6, 11. ResultsThe median follow-up period was 29 months (range 6–78) and median engraftment time 10 days (range 8–17). Thirty-one patients (75.6%) were treated for infections, with 20 of these on antifungals for preexisting infections. There were two graft rejections and 10 (24.4%) deaths, with three intracranial hemorrhages, two rejections with infection, three cases of refractory GVHD (acute/overlap syndrome) with cytomegalovirus reactivation, and two invasive fungal infections. Overall incidence of acute GVHD was 39% with 2 grade IV cases. Ten (25%) cases developed chronic GVHD, with extensive GVHD in four. ConclusionWith more experience using shortened course of ATGAM, HLA-matched donor transfusions, and availability of newer antifungals, we have been able to decrease PBSCT-related mortality. Further improvement will be possible with early referrals.

Donor-Specific HLA Antibodies: Risk Factors and Outcomes After Kidney Transplantation

BackgroundAnti–human leukocyte antigen antibodies (HLA Abs) have been associated with reduced kidney allograft survival. Our aim was to analyze the prevalence and impact on allograft function of donor-specific HLA antibodies (DSA) among a cohort of kidney transplant recipients. Patients and MethodsThe 321 recipients had received deceased-donor kidneys followed for a median of 70 ± 43 months. We performed a cross-sectional analysis of the presence of HLA Abs with the use of Luminex technology. ResultsFifty patients (15.6%) displayed HLA Abs after transplantation including 21 (6.7%) as de novo HLA Abs. Eight patients (2.5%) developed DSA, and 42 (13%) showed no DSA. We compared 3 groups of patients: with DSA, without DSA, and without HLA sensitization. The DSA patients were younger (P = .03) with a higher percentage of men (P = .00), and having received less frequent induction treatment with basiliximab or thymoglobulin (P = .02). Patients without DSA revealed a higher percentage of pretransplantation HLA sensitization (P = .00), more pretransplantation transfusions (P = .08), and more frequent retransplantations (P = .00). The incidence of acute rejections was higher for DSA patients (P = .02) than for the other 2 groups, behaving as an independent risk factor (relative risk, 4.7; 95% confidence interval, 1.1–18.8; P = .03). Graft survival at 5 years was lower among patients with compared to those without HLA Abs (P = .00). ConclusionsHLA donor-specific sensitization, an uncommon situation in our study, was associated with younger male recipients and less induction treatment. An acute rejection episode was an independent risk factor for the development of DSA; therefore, we think that monitoring of HLA Abs should be included in evaluation of the early postransplantation period.

Transfusion sanguine et transplantation

Pretransplant blood transfusion remains a controversial subject and its history can summarize the last 40 years of transplantation. Until 1971, transfusions were widely used in patients awaiting transplantation, especially due to the anemia induced by the chronic renal dysfunction. Then, a noxious effect of preformed anti-HLA antibodies on renal grafts survival was reported and pretransplant transfusions were stopped. Between 1972 and 1977, improvement of renal graft survival in patients who received pretransplant transfusions was noted. Therefore, from 1978 on, a systematic policy of pretransplant transfusions was adopted by almost all centres of transplantation. During the eighties, it was again abandoned for several reasons: absence of graft survival improvement in patients treated by cyclosporine, HLA immunization leading to an increased incidence of acute graft rejection, risk of viral diseases transmission and human recombinant erythropoietin development. The lack of improvement in graft survival for ten years has been leading the transplant community to look for antigen-specific immunosuppressive strategies to achieve transplantation tolerance. Donor-specific transfusion may have clinical benefits, as long-term grafts survival improvement, through modulation of the recipient's cellular immune system and has been recently reconsidered, especially before living donor transplantation. The immunological mechanisms inducing a tolerance-gaining effect of transfusions are still misunderstood, but the recent discovery of immunomodulatory effects of the apoptotic cells present in cellular products could enlighten our comprehension of pretransplant transfusions benefits and could help to develop specific tolerance induction strategies in solid organ transplantation.

Blood transfusions in kidney transplant candidates are common and associated with adverse outcomes

Surprisingly, there are no data regarding transfusion frequency, factors associated with transfusion administration in patients on the kidney transplant waiting list, or transfusion impact on graft and recipient outcomes. We used United States Renal Data System data to identify 43,025 patients added to the waiting list in 1999-2004 and followed through 2006 to assess the relative risk of post-listing transfusions. In 69,991 patients who underwent transplants during the same time period, we assessed the association between pre-transplant transfusions and level of panel-reactive antibody (PRA) at the time of transplant, and associations between PRA and patient outcomes. The three-yr cumulative incidence of transfusions was 26% for patients added to the waiting list in 1999, rising to 30% in 2004. Post-listing transfusions were associated with a 28% decreased likelihood of undergoing transplant, and a more than fourfold increased risk of death. There was a graded association between percent PRA at the time of transplant and adjusted risk of death-censored graft failure, death with function, and the combined event of graft failure and death. These data demonstrate that transfusions remain common and confirm the adverse association between transfusions and PRA, and high PRA and inferior graft and patient outcomes.

Prognostic Impact of Pretransplant Transfusion Amount on Outcome After Allogeneic Stem Cell Transplantation In Adult Patients with Severe Aplastic Anemia

AbstractAbstract 3503 Background:Aplastic anemia (AA) is a life-threatening bone marrow failure disorder. Therefore, many patients with AA require blood transfusions as supportive management. Regular transfusions of packed red cell (PRC) lead to the development of iron overload, which is known to increase the risk of complications after stem cell transplantation (SCT). However, the prognostic impact of pretransplant transfusion history of PRC on outcome in AA has not been completely analyzed. We investigated the impact of pretransplant transfusion amount of PRC on outcome after allogeneic SCT in severe AA (SAA). Methods:221 adult patients with SAA who underwent allogeneic SCT between January 1995 and August 2007 who had not received optimal iron chelating therapy were selected for retrospective analysis. Results:221 patients were divided into two groups according to the mean amount of pretransplant transfusion (32 PRC units): receiving less than 32 PRC units (n=164), >32 PRC units (n=57) before SCT. The median follow-up duration of survivors after SCT was 47.9 (39.5-56.2) months in ≤32 PRC units of transfusion group and 42.8 (39.7-45.9) months in >32 PRC units of transfusion group. Primary engraftment was achieved in all, but 13 patients (9/164 patient, 5.5% in the ≤32 PRC units of transfusion group, 4/57 patients, 7% in the >32 PRC units of transfusion group, P=0.745) developed secondary graft failure. Acute GVHD (grade II-IV) developed in 27.4% in ≤32 PRC units of transfusion group and 42.1% in >32 PRC units of transfusion group (P=0.04), and extensive type of chronic GVHD occurred in 20.7% and 26.3% among evaluable patients, respectively. In the comparison between two groups, higher pretransplant transfusion group has significantly increased risk of transplant-related mortality (TRM) (<32 PRC units of transfusion: 8.2% vs >32 PRC units of transfusion: 25.2%, P=<0.000), and lower overall survival (OS) (91.8% vs 75.2%, P=0.001) than those with lesser transfusion history. Multivariate analysis revealed that higher pretransplant PRC amount [HR (95% CI) 3.09 (1.44-6.63), P=0.004] and donor type (related vs unrelated) [HR 2.41 (95% CI) (1.10-5.27), P=0.028] were independent prognostic factor for affecting OS. Conclusion:These results indicate that higher pre-transplant transfusion history of PRC was associated with increased TRM and decreased OS, and it has shown to have a negative impact on outcome after SCT in SAA. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Bridge to Heart Transplantation with Left Ventricular Assist Device Versus Inotropic Agents in Status 1 Patients

Left ventricular assist devices (LVADs) are commonly used for critically ill patients awaiting heart transplantation, although their effect on long-term outcomes, relative to inotropic support alone, is still debated. Data from Status 1 patients who underwent heart transplantation at our institution between 1990 and 2005 were reviewed (n = 180). They were divided into two groups: those who underwent LVAD implantation as a bridge to transplant (n = 31) and those treated with inotropic agents without the support of LVAD (n = 149). They were compared in terms of demographics and clinical outcome. Both groups were similar in terms of patient and donor demographics. Relative to the inotrope group, the LVAD group did have a longer ischemic time (p = 0.032), a greater incidence of pretransplant transfusion (p < 0.00001), and a greater maximum level of pretransplant panel reactive antibodies (p < 0.001). Creatinine at listing significantly improved in LVAD patients awaiting transplantation (p < 0.0001). Comparisons of 5-year survival in addition to freedom from posttransplant infection, malignancy, revascularization, and acute rejection did not show significant difference between the two groups. The LVAD group did benefit from increased freedom from chronic rejection compared to the inotrope group (p = 0.049). Stepwise Cox Regression did not identify any independent factors affecting patient survival during the first 5 years after transplant. Status 1 patients successfully bridged to heart transplantation with LVADs had similar long-term clinical outcomes compared to those treated with inotropic agents.

Effects of Blood Transfusions Given After Renal Transplantation

Human leukocyte antigen (HLA) antibodies produced after transplantation are frequently measured in transplant recipients, because they are strongly associated with humoral rejection and graft loss. However, antibodies can be induced by posttransplant blood transfusions rather than by the graft, casting doubts about the possible role of antibodies in a patient with graft dysfunction. We recorded the posttransplant transfusions in 746 patients transplanted during a 6-year period. Rejection episodes were evaluated after exclusion of patients who were transfused proximate to the time of rejection. Specimens for solid-phase HLA antibody testing were available in 199 patients. The frequency of transfusions was 45%, but it was higher in deceased donor transplants (51%) than in live donor transplants (30%). Almost 80% of the transfusions were given during the first month after transplant. However, the incidence of posttransplant antibodies was similar in patients transfused and not transfused, and only 1 of 12 patients who received more than 10 transfusions produced antibodies. There was no evidence that posttransplant antibodies not directed to donor antigens were triggered by transfusions. The incidence of rejection episodes, allograft nephropathy, and graft loss was slightly more in transfused patients but the differences were not statistically significant. When HLA antibodies are detected posttransplant, they are likely induced by the graft rather than by any transfusions the patient may have received. The results suggest that posttransplant transfusions do not have the sensitizing or down-regulatory effects of pretransplant transfusions.

Progressive Multifocal Leukoencephalopathy and Use of Mycophenolate Mofetil After Kidney Transplantation

Mycophenolate mofetil (MMF) use may be associated with progressive multifocal leukoencephalopathy (PML). We conducted a retrospective cohort study of 32,757 renal transplant recipients using the United States Renal Data System kidney transplant files for the incidence, prognosis, and clinical features associated with PML occurring after kidney transplant. Subjects were transplanted from January 1, 2000 to July 31, 2004 and followed through December 31, 2004. The incidence density of PML in MMF users was 14.4 cases/100,000 person-years at risk versus 0 for non-MMF users (P=0.11) by log rank test. Factors significantly associated with PML were BK virus infection (22.2% vs. 1.1%), pretransplant transfusion (75% vs. 34%), panel reactive antibody more than 20% (56% vs. 14%), and use of antirejection medications in the first year (33% vs. 9.2%), all P less than 0.05. PML is rare in the renal transplant population. There was no significant association between PML and MMF, but MMF use in this cohort is too high to accurately assess an association.

Hematopoietic Recovery and Overall Survival after HLA-Matched Sibling Transplants for Older Patients with Severe Aplastic Anemia (SAA).

Long-term survival after HLA-matched sibling transplants for SAA is 80–90% in patients <20 years at transplantation. Survival in older patients is lower. Herein, we report risk factors affecting hematopoietic recovery and long-term survival in older patients with SAA after HLA-matched sibling transplants. All transplantations occurred in 1991–2004. Before analysis of risk factors affecting survival we determined the ages at which survival rates differed significantly. Significant differences in survival rates were observed in the following age groups: <20 years (n=818), 20–40 years (n=618) and >40 years (n=127). Beyond 40 years, we were unable to find an age effect despite 44% of patients in this group being ≥50 years. Patients older than 40 years were more likely to have received >50 red blood cell transfusions, immunosuppressive therapy (65% vs. 50% in patients <40 years), have poor performance scores at transplantation, a longer waiting period to transplant (40% received transplants beyond 6 months from diagnosis compared to < 25% in the other groups) and more likely to receive peripheral blood grafts. Neutrophil recovery rates (day-28) did not differ in the three groups; 83%, 88% and 86% in patients aged <20 years, 20–40 years and >40 years, respectively. Recovery was more likely with peripheral blood transplants (odds ratio [OR] 1.96, p=0.022). Neutrophil recovery was lower with cyclophosphamide alone (OR 0.50, p=0.002) and fludarabine-containing conditioning regimens (OR 0.44, p=0.033). In contrast, age at transplantation was associated with platelet recovery (day- 100). Recovery was lowest in patients >40 years (89%) compared to 94% in patients <20 years (p<0.001) and 94% in patients 20–40 years (p=0.004). Platelet recovery was higher in patients with performance scores 90–100, OR 2.22, p<0.001, independent of age. As expected acute and chronic graft-versus-host disease (GVHD) risks were higher in those ≥20 years. We did not observe differences in acute (RR 1.42, p=0.089) and chronic GVHD (RR 1.21, p=0.354) risks between patients aged 20–40 years and >40 years. As shown in the Table below mortality risks increased with age. The 5-year probabilities of overall survival after adjusting for performance score, preparatory regimen, interval from diagnosis to transplantation, donor-recipient sex match and cytomegalovirus serostatus, factors affecting overall survival, were 81%, 72% and 53% in patients aged <20 years, 20–40 years and >40 years, respectively (p<0.001). Independent of age, mortality rates were higher in patients with poor performance score (RR 1.92, p<0.001), recipients of transplant preparatory regimens other than cyclophosphamide with or without anti-thymocyte globulin (RR 1.52, p=0.004), >6 months from diagnosis to transplantation (RR 1.50, p=0.001) and female recipients receiving grafts from male donors (RR 1.57, p=0.001). Mortality rates were lower when both donor and recipient were CMV sero-negative (RR 0.53, p<0.001). In conclusion, survival after transplantation in patients >40 years was significantly lower compared to younger patients. Longer interval from diagnosis to transplantation, higher numbers of pretransplant red blood cell transfusions and poor performance scores at transplantation may explain the inferior outcomes in patients >40 years. Use of peripheral blood grafts did not affect overall survival (p=0.169). The data suggest there is a need to improve survival in older patients; early referral for transplantation and improved supportive care may improve outcomes.OutcomeRelative RiskP-valueOverall mortality20–40 years vs. <20 years1.63<0.001>40 years vs. <20 years3.25<0.001>40 years vs. 20–40 years2.00<0.001

Pre-Transplant Comorbidity as An Outcome Predictor in Hematopoietic Cell Transplantation for Severe Aplastic Anemia

A new hematopoietic cell transplantation specific comorbidity index (HCT-CI), which was modeled to effectively capture comorbidity and predict post-transplant outcomes, has been evaluated in a cohort of patients with a variety of hematologic disorders. In this study, we applied the HCT-CI to 77 patients with severe aplastic anemia who underwent HCT at the Asan Medical Center, Seoul, Korea between February 1995 and September 2007. Pre-transplant HCT-CI score was calculated in each patient using the clinico-pathologic data, which were retrieved from Asan Medical Center Bone Marrow Transplantation Registry Database. HCT-CI score was 0 in 54 patients (70%), 1 in 16 (21%), 2 in four (5%), and 4 in one (1%). The most prevalent comorbidity captured by the HCT-CI was infection (n=11) followed by arrhythmia (n=6). During a median follow-up period of 54.4 months (range, 4.0 to 159.0 months), 19 patients died and 16 experienced primary or secondary graft failure. The 5-year probabilities of overall survival (OS) and event-free survival (EFS) were 73.4% and 63.3%, respectively. OS and EFS were significantly different according to HCT-CI score; OS 86.6% and EFS 74.3% in patients with score 0 versus 43.5% and 38.5% in those with score 1 or more (P<0.001 for OS and P=0.001 for EFS). Other significant prognostic factors for OS were age (<30 years vs. ≥30, 90.8% vs. 58.3%, P=.002), pre-transplant transfusion amount (<50 units vs. ≥50, 93.0% vs. 61.0%; P=.005) and time from diagnosis to HCT (<120 days vs. ≥120, 85.2% vs. 61.4%; P=.013), and prognostic factors for EFS were age (<30 years vs. ≥30, 81.0% vs. 48.4%, P=.003) and time from diagnosis to HCT (<120 days vs. ≥120, 77.4% vs. 48.3%; P=.007). Multivariate analysis after adjustment for other variables demonstrated that HCT-CI score (HR 10.022, P<.001 for OS; HR 4.644, P<.001 for EFS), age (HR 8.447, P=.002 for OS; HR 4.060, P=.003 for EFS), time from diagnosis to HCT (HR 5.783, P=.002 for OS; HR 3.956, P=.002 for EFS) were independently significant prognostic factors for both OS and EFS. In conclusion, our data indicate that the presence of pre-transplant comorbidity assessed by HCT-CI may predict worse outcomes after HCT in severe aplastic anemia.

Factors affecting kidney‐transplant outcome in recipients with lupus nephritis

Factors associated with outcome in renal transplant recipients with lupus nephritis have not been studied. Using the data from the United States Renal Data System of patients transplanted between January 1, 1995 through December 31, 2002 (and followed through December 31, 2003) (n = 2882), we performed a retrospective analysis of factors associated with long-term death-censored graft survival and recipient survival. The number of pretransplant pregnancies incrementally increased the risk of graft failure [hazard ratio (HR) 1.54, p < 0.05] in the entire subgroup of females and in the subgroup of recipients aged 25-35 yr. Recipient and donor age had an association with both the risk of graft failure (HR 0.96, p < 0.001; HR 1.01, p < 0.005) and recipient death (HR 1.04, p < 0.001; HR 1.01, p < 0.05). Greater graft-failure risk accompanied increased recipient weight (HR 1.01, p < 0.001); African Americans compared with whites (HR 1.55, p < 0.001); greater Charlson comorbidity index (HR 1.17, p < 0.05); and greater panel reactive antibody (PRA) levels (HR 1.06, p < 0.001). Pretransplant peritoneal dialysis as the predominant modality had an association with decreased risk of graft failure (HR 0.49, p < 0.001), while prior transplantation was associated with greater risk of graft failure and recipient death (HR 2.29, p < 0.001; HR 3.59, p < 0.001, respectively) compared with hemodialysis (HD). The number of matched human leukocyte antigens (HLA) antigens and living donors (HR 0.92, p < 0.05; HR 0.64, p < 0.001, respectively) was associated with decreased risk of graft failure. Increased risk of graft failure and recipient death was associated with nonuse of calcineurin inhibitors (HR 1.89, p < 0.005; HR 1.80, p < 0.005) and mycophenolic acid (MPA) (including mycophenolate mofetil and MPA) or azathioprine (HR 1.41, p < 0.05; HR 1.66, p < 0.01). Using both cyclosporine and tacrolimus was associated with increased risk of graft failure (HR 2.09, p < 0.05). Using MPA is associated with greater risk of recipient death compared with azathioprine (HR 1.47, p < 0.05). In renal transplant recipients with lupus nephritis, multiple pregnancies, multiple blood transfusions, greater comorbidity index, higher body weight, age and African American race of the donor or recipient, prior history of transplantation, greater PRA levels, lower level of HLA matching, deceased donors, and HD in pretransplant period have an association with increased risk of graft failure. Similarly, higher recipient and donor age, prior transplantations, and higher rate of pretransplant transfusions are associated with greater risk of recipient mortality. Using neither cyclosporine nor tacrolimus or using both (compared with tacrolimus) and neither MPA nor azathioprine (compared with azathioprine) was associated with increased risk of graft failure and recipient death. Using MPA is associated with greater risk of recipient death compared with azathioprine. Testing these results in a prospective study might provide important information for clinical practice.

Perioperative blood transfusions for the recurrence of colorectal cancer.

The improvement of renal allograft survival by pre-transplantation transfusions alerted the medical community to the potential detrimental effect of transfusions in patients being treated for cancer. The present meta-analysis aims to evaluate the role of perioperative blood transfusions (PBT) on colorectal cancer recurrence. This is accomplished by validating the results of a previously published meta-analysis (Amato 1998); and by updating it to December 2004. Published papers were retrieved using Medline, EMBASE, the Cochrane Library, controlled trials web-based registries, or the CCG Trial Database. The search strategy used was: {colon OR rectal OR colorectal} WITH {cancer OR tumor OR neoplasm} AND transfusion. The tendency not to publish negative trials was balanced by inspecting the proceedings of international congresses. Patients undergoing curative resection of colorectal cancer (classified either as Dukes stages A-C, Astler-Coller stages A-C2, or TNM stages T1-3a/N0-1/M0) were included if they had received any amount of blood products within one month of surgery. Excluded were patients with distant metastases at surgery, and studies with short follow-up or with no data. A specific form was developed for data collection. Data extraction was cross-checked, using the most recent publication in case of repetitive ones. Papers' quality was ranked using the method by Evans and Pollock. Odds ratios (OR, with 95% confidence intervals) were computed for each study, and pooled estimates were generated by RevMan (version 4.2). When available, data were stratified for risk factors of cancer recurrence. The findings of the 1998 meta-analysis were confirmed, with small variations in some estimates. Updating it through December 2004 led to the identification of 237 references. Two-hundred and one of them were excluded because they analyzed survival (n=22), were repetitive (n=26), letters/reviews (n=66) or had no data (n=87). Thirty-six studies on 12,127 patients were included: 23 showed a detrimental effect of PBT; 22 used also multivariable analyses, and 14 found PBT to be an independent prognostic factor. Pooled estimates of PBT effect on colorectal cancer recurrence yielded overall OR of 1.42 (95% CI, 1.20 to 1.67) against transfused patients in randomized controlled studies. Stratified meta-analyses confirmed these findings, also when stratifying patients by site and stage of disease. The PBT effect was observed regardless of timing, type, and in a dose-related fashion, although heterogeneity was detected. Data on surgical techniques was not available for further analysis. This updated meta-analysis confirms the previous findings. All analyses support the hypothesis that PBT have a detrimental effect on the recurrence of curable colorectal cancers. However, since heterogeneity was detected and conclusions on the effect of surgical technique could not be drawn, a causal relationship cannot still be claimed. Carefully restricted indications for PBT seems necessary.

Combination Treatment with Donor-Specific Transfusions and Cyclosporine A Induces Long-Term Survival of Cardiac Allografts in Miniature Swine

To evaluate whether pretransplant donor-specific transfusions (DST) can induce tolerance to cardiac allografts in large animals, heterotopic cardiac transplants were performed across a class I MHC barrier in inbred miniature swine. Experimental animals received two DSTs, each containing 1.4x10 viable peripheral blood mononuclear cells, 14 and 7 days prior to transplantation together with a 12-day course of cyclosporine (CyA) (13 mg/kg IV) starting on postoperative day (POD) 0. Untreated (n=2) and DST-only (n=2) treated control animals rejected between POD 6 and 8. Animals treated with CyA alone (n=3) exhibited graft survival to 53, 52 and 59 days. In contrast, the combination of DST and CyA (n=3) led to stable graft function for >200 days. Long-term survivors maintained peripheral CML response against donor antigen. Following DSTs, the donor-specific proliferative response of CD8+ recipient T cells was significantly increased (P=0.011), and a significant number of CD8+ T cells underwent apoptosis (10.1% on POD 0; 5.2% on POD -14; P=0.04). None of the DST-treated animals developed donor-specific antibodies. These results are the first to demonstrate the ability of DST to induce operational tolerance to cardiac allografts in large animals, and they suggest that peripheral mechanisms of tolerance mediate this effect.

Is Bridging to Transplantation With a Left Ventricular Assist Device a Risk Factor for Transplant Coronary Artery Disease?

Left ventricular assist device (LVAD) support is associated with coagulopathy, bleeding, increased blood transfusion, and increased anti-HLA antibody production. Increased anti-HLA antibody production is associated with early transplant rejection, transplant coronary artery disease (CAD), and decreased post-transplant survival rates. We asked whether bridging to transplantation with an LVAD increases the risk of transplant CAD. We reviewed data for all adults (>18 years old) who underwent heart transplantation at our institution between 1988 and 2000. After exclusion of transplant recipients who survived <3 years, we divided the remaining cohort into 2 groups: those bridged to transplantation with LVADs (mean duration of support, 149 +/- 107 days, n = 29) and those in United Network for Organ Sharing Status 1 bridged to transplantation without LVADs (controls, n = 86). We compared groups in terms of disease cause, age, sex, donor age, panel-reactive antibody testing, crossmatching, pre- and post-transplant cholesterol concentrations, diagnosis of diabetes mellitus or treated hypertension, infections, calcium channel blocker use, transplant rejection, ischemic time, cytomegalovirus infection, pre-transplant transfusion, and incidence of transplant CAD (defined as any coronary lesion identified by coronary angiography). We considered p < 0.05 to be significant. The bridged and control groups were similar in all respects except mean ischemic time (217 +/- 58 minutes vs 179 +/- 67 minutes, p = 0.007), post-transplant cholesterol concentration (212 +/- 55 mg/dl vs 171 +/- 66 mg/dl, p = 0.007), and pre-transplant transfusion incidence (100% vs 22%, p < 0.001). The incidence of transplant CAD was similar in both groups during a 3-year follow-up period (28% vs 17%, p = 0.238) and during total follow-up (34% vs 35%, p = 0.969). Multivariate logistic regression analysis identified cholesterol concentration at 1 year after transplantation as a significant predictor of CAD at 3 years after heart transplantation (p = 0.0029, odds ratio = 0.984). Bridging to transplantation with an LVAD does not increase the risk of transplant CAD. Nevertheless, aggressive prophylactic therapy to minimize potential risk factors for transplant CAD, such as increased cholesterol concentration, is warranted in all transplant recipients.

IDEC-131 (Anti-CD154), Sirolimus and Donor-Specific Transfusion Facilitate Operational Tolerance in Non-Human Primates

CD154-specific antibody therapy prevents allograft rejection in many experimental transplant models. However, initial clinical transplant trials with anti-CD154 have been disappointing suggesting the need for as of yet undetermined adjuvant therapy. In rodents, donor antigen (e.g., a donor blood transfusion), or mTOR inhibition (e.g., sirolimus), enhances anti-CD154's efficacy. We performed renal transplants in major histocompatibility complex-(MHC) mismatched rhesus monkeys and treated recipients with combinations of the CD154-specific antibody IDEC-131, and/or sirolimus, and/or a pre-transplant donor-specific transfusion (DST). Therapy was withdrawn after 3 months. Triple therapy prevented rejection during therapy in all animals and led to operational tolerance in three of five animals including donor-specific skin graft acceptance in the two animals tested. IDEC-131, sirolimus and DST are highly effective in preventing renal allograft rejection in primates. This apparently clinically applicable regimen is promising for human renal transplant trials.

Tolerance to cardiac allografts in miniature swine using donor-specific transfusions combined with cyclosporine but not with rapamycin

To evaluate the effect of pretransplant donor-specific transfusion (DST)combined with CyA and rapamycin on tolerance induction to cardiac allografts in a large animal model.

PRE-TRANSPLANT DONOR-SPECIFC TRANSFUSIONS COMBINED WITH CYCLOSPORINE BUT NOT WITH RAPAMYCIN INDUCE TOLERANCE TO MHC CLASS I-MISMATCHED CARDIAC ALLOGRAFTS IN MINIATURE SWINE

P1125 Aims: To evaluate the effect of pretransplant donor-specific transfusion combined with cyclosporine A and rapamycin on tolerance induction to cardiac allografts in a clinically relevant large-animal model. Methods: Heterotopic cardiac transplants were performed across a major histocompatibility complex (MHC) class I barrier in MHC-inbred miniature swine. Experimental animals were treated with two donor-specific transfusions (DSTs), each containing 1.4x108 viable peripheral blood mononuclear cells, 14 and 7 days prior to heart transplantation. All animals received a 12-day course of cyclosporine (CyA) (trough level 300-800 ng/ml) or rapamycin (RPM) (trough level 10-20 ng/ml) starting on post-operative day (POD) 0. Control groups received CyA or RPM alone, DST alone or no treatment. Cell mediated lympholysis (CML) assays were performed at regular intervals. T cell priming and activation induced cell death (AICD) were assessed by carboxyfluoroscein succinimidyl ester (CFSE) proliferation assays and Annexin V staining. Results: Untreated (n=2) and DST-only (n=2) treated control animals rejected between POD 6 and 8. Animals treated with CyA (n=3) or RPM (n=3) alone exhibited graft survival to 53, 52 and 59 days or 41, 50 and 53 days, respectively. In contrast, DST-pretreatment combined with CyA (n=3) led to stable graft function for >200 days in all animals. Grafts in recipients treated with pretransplant DST and RPM (n=4) survived 52, 45, 100 and >200 days. Like the controls, long-term acceptors in the DST+CyA group and DST+RPM group mostly maintained peripheral CML response against donor and third party antigen. Following DSTs, the donor-specific proliferative response of CD8+ recipient T cells was significantly increased on CFSE assay (p=0.011), and a significant number of recipient CD8+ T cells underwent apoptosis (10.1% on POD 0 versus 5.2% on POD –14; p=0.04). Conclusions: The combination of pre-transplant DST and a short course of CyA consistently prolongs the survival of MHC class I disparate cardiac allografts in miniature swine. The sustained peripheral anti-donor CML response and the fact that alloreactive T cells were primed by the DST prior to transplantation suggest an active regulatory mechanism rather than peripheral deletion. In contrast, rapamycin did not demonstrate with the tolerogenic effect of pretransplant DST potentially because it failed to achieve appropriate regulatory cells.

FACTORS PREDISPOSING TO POST-RENAL TRANSPLANT ERYTHROSIS.A RETROSPECTIVE STUDY.

P278 Aims: We conducted a retrospective study on 56 consecutive patients who had a kidney transplant with draft function for over 3 months to evaluate the prevalence of erythrosis following renal transplantation (PTE) and its potential risk. Methods: A total of 56 renal transplant recipients who received a kidney between 1985 and 2001, with a graft that functioning longer than 3 months were retrospectively studied until 31/12/2002. All patients were given prophylactic therapy with ATG. Maintenance immunosuppression consisted of three-drug therapy with prednisone-cyclosporine-azathioprine. Rejection episodes were treated with methylprednisolone IV or OKT3. Critera’s diagnostic of PTE were following : hematocrit (Ht) > 52% and hemoglobin (Hb) > 18 G/dl in all males, and in females Ht >48% andHb >16 G/dl. 24 non-polycythemic patients matced for sex, age and renal function were used as case control. The variables compared between polycythemic and control group were original disease, nephrectomy of the native kidneys (1 or two), duration of dialysis, number of pretransplant transfusions, treatment with rH-EPO, pretransplant Hb, acute rejection episodes, immunosuppressive therapy, iron supplementation, post-transplant HTA and treatment with ACEI. Statistical analysis data are expressed as mean+- SD and analyzed using the chi2, Fischer and Mann-Whitny tests. Results: True erythrosis developed in 14 of the 56 patients 3-60 months post transplantation for a prevalence of 25%. PTE is an early complication and more common in man. The time for correction of anemia was significantly shorte in the PTE group. PTE was significantly correlated with a good graft function, a short dialysis duration and no rejection episode. Repeated phlebotomies were performed for 3 patients to maintain hematocrit below 50%. 4 patients recovered spontaneously and none had a thrombotic event. ACEI treatment was used to correct pte in 7 patients and Theophyllin was given to 3 patients. Conclusions: We conclude that true erythrosis is prevalent in cyclosporine-treated renal transplant patients. PTE seems to be an idiopathic erythrosis. ACEI treatment is effective and save.

Use of cyclosporine in renal transplantation

The first cyclosporine trials in renal transplantation began in Cambridge in 1978. Between 1982 and 1985 several large multicenter trials and the reports from large series of patients evidenced that cyclosporine was a major advance in the prevention of acute rejection episodes and in improving short-term and long-term graft survival. Cyclosporine also showed the capacity to mitigate immunologic risk factors, HLA mismatching, and lack of pretransplant transfusions. However, cyclosporine has the serious defect of being nephrotoxic. Induction therapy with OKT3, polyclonal antibodies, and more recently with anti IL-2R monoclonal antibodies allowed the delay of introduction cyclosporine in patients showing posttransplant graft dysfunction. Other relatively unsuccessful attempts for overcoming cyclosporine nephrotoxicity were made before the association of new xenobiotics such as mycophenolate mofetil or sirolimus permitted cyclosporine doses to be reduced. These combinations reduce acute rejection incidence to below 20%, with its consequent positive impact on long-term graft outcome and also allow a safer steroid sparing and withdrawal early posttransplantation. Also, the association of cyclosporine with other new compounds such as the lymphocyte homing FTY20 or the peripheral lymphocyte-depleting Campath-1-IgG is currently under clinical investigation. Cyclosporine's future place is yet to be established in the new era of immunosuppression.