The effect of HLA mismatches, shared cross-reactive antigen groups, and shared HLA-DR antigens on the outcome after pediatric liver transplantation.

The aim of this study was to analyze the effect of human leukocyte antigen (HLA) class I and HLA-DR mismatching, sharing cross-reactive antigen groups (CREGs), and sharing HLA-DR antigens on the outcome after pediatric liver transplantation. Outcome parameters were graft survival, acute rejection, and portal fibrosis. A distinction was made between full-size (FSLTx) and technical-variant liver transplantation (TVLTx). A total of 136 primary transplants were analyzed. The effect of HLA on the outcome parameters was analyzed by adjusted multivariate logistic and Cox regression analysis. HLA mismatches, shared CREGs, and shared HLA-DR antigens affected neither overall graft survival nor survival after FSLTx. Survival after TVLTx was superior in case of 2 mismatches at the HLA-DR locus compared to 0 or 1 mismatch (P = 0.01) and in case of no shared HLA-DR antigen compared to 1 shared HLA-DR antigen (P = 0.004). The incidence of acute rejection was not influenced by HLA. The incidence of portal fibrosis could be analyzed in 62 1-yr biopsies and was higher after TVLTx than FSLTx (P = 0.04). The incidence of portal fibrosis after TVLTx with 0 or 1 mismatch at the HLA-DR locus was 100% compared to 43% with 2 mismatches (P = 0.004). After multivariate analysis, matching for HLA-DR and matching for TVLTx were independent risk factors for portal fibrosis. In conclusion, an overall beneficial effect of HLA matching, sharing CREGs, or sharing HLA-DR antigens was not observed. A negative effect was present for HLA-DR matching and sharing HLA-DR antigens on survival after TVLTx. HLA-DR matching might be associated with portal fibrosis in these grafts.     

Survival benefit of cardiopulmonary bypass support in bilateral lung transplantation for emphysema patients

BACKGROUND: This study is designed to examine a possible association of cardiopulmonary bypass (CPB) support and outcome of lung transplantation in a well-balanced group of emphysema patients. METHODS: We performed a retrospective analysis of 62 consecutive primary bilateral lung transplantations for emphysema. Risk factors for their possible association with patient survival were analyzed by multivariate logistic regression. RESULTS: The use of CPB support was associated with improved survival (odds ratio=0.25; P=0.038). The actuarial survival at 1 year was 97% for patients treated with CPB and 77% for patients treated without CPB support. In 28 patients (45%), 2 human leukocyte antigen (HLA)-DR mismatches between donor and recipient occurred, whereas 34 patients had 0 or 1 HLA-DR mismatches. The use of CPB support in the group with two HLA-DR mismatches was associated with improved survival (odds ratio=0.06; P=0.020). This association was not present in the group with 0 or 1 HLA-DR mismatches. CONCLUSIONS: These results demonstrate a significant survival benefit of CPB support during bilateral lung transplantation in emphysema patients. The difference in survival benefit of CPB support between the patients with 0 or 1 HLA-DR mismatches and the patients with 2 HLA-DR mismatches indicates that the immunosuppressive effect of CPB support might be responsible for this survival benefit. The underlying immunological mechanism might be important in the future treatment of organ transplantation.     

Increased immunogenicity and cause of graft loss of old donor kidneys.

Donor age was identified recently as a major factor that determines long-term outcome after transplantation, but the mechanism that is responsible for increased graft loss of old donor kidneys is unknown. The influence of donor age on graft survival was assessed retrospectively in 514 consecutive first cadaveric transplants that were treated with cyclosporine maintenance immunosuppression. Donor age > or =50 yr (relative risk [RR] = 1.7; 95% confidence interval [CI], 1.2 to 2.6), acute rejection (RR = 2.0; 95% CI, 1.3 to 3.0), and type of rejection (RR = 3.3; 95% CI, 2.0 to 5.3) had a significant impact on graft survival. However, when subsets of patients who entered subsequent intervals after transplantation were analyzed, donor age was not an independent predictive factor of graft loss. Donor age (RR = 1.53; 95% CI, 1.19 to 1.98), human leukocyte antigen-DR mismatch (RR = 2.28; 95% CI, 1.78 to 2.92), and recipient age (RR = 1.34; 95% CI, 1.05 to 1.72) were associated significantly with acute rejection episodes. Delayed graft function alone was not associated independently with the occurrence of early acute rejection (RR = 1.24; 95% CI, 0.96 to 1.61). The timing of the rejection episodes of old donor kidneys was not different, and the excess rejection prevalence was attributable entirely to interstitial (grade I) types of rejection. Interstitial rejection episodes in kidneys from old donors had a significant (P < 0.05) negative impact on graft survival. Beyond the first year, poor renal function and proteinuria were significant risk factors for graft loss, regardless of rejection. Our data fit best the hypothesis that increased graft loss of older donor kidneys results from an increased incidence of acute interstitial rejection episodes in the early posttransplantation months. It is proposed that kidneys from older donors are more immunogenic than kidneys from young donors and that acute rejection episodes result in functional deterioration. Contrary to interstitial rejection in kidneys from younger donors, kidneys from old donors seem to have an impaired ability to restore tissue.     

Heterotopic vs. orthotopic liver transplantation for chronic liver disease: a case-control comparison of short-term and long-term outcomes.

Between 1986 and 1990 we performed heterotopic liver transplantation (HLT) in 17 patients with chronic liver disease. In spite of theoretical advantages and favorable short-term results, we abandoned HLT because of doubts about the long-term outcome and the improved results of standard orthotopic liver transplantation (OLT). There are, however, no studies comparing the long-term survival after HLT and OLT for chronic liver disease. We performed a case-control study of HLT vs. OLT, with long-term patient and graft survival as the main outcome measures. Known confounders and differences in baseline characteristics between HLT and OLT patients were corrected for. At 1 year, 5 of the 17 HLT patients had died, compared with 9 of the 34 OLT patients (relative risk [RR], 1.15; 95% confidence interval [CI], 0.33-4.02; P = 0.83). After correction for confounders, the long-term risk of graft failure (RR, 18.0; 95% CI, 1.5-223.5; P = 0.02) and of death (RR, 5.2; 95% CI, 0.8-34.8; P = 0.09) was higher after HLT than after OLT. The main causes of graft loss and death at more than 1 year after HLT were de novo malignancies and a variety of biliary complications. In conclusion, our data, from 1 of the largest single-center series of HLTs available, showed no significant difference between HLT and OLT in 1-year survival. However, the long-term outcome of HLT was inferior. HLT cannot be recommended as an alternative to OLT for any of the indications we studied, even though only 1 of the late deaths was definitely related to the heterotopic technique.     

Respiratory viruses and chronic rejection in lung transplant recipients.

BACKGROUND; Chronic rejection manifested as obliterative bronchiolitis (OB) and bronchiolitis obliterans syndrome (BOS) continue to be major causes of morbidity and mortality after lung transplantation. Community respiratory virus (CRV) infection, including respiratory syncytial virus, parainfluenza virus, and influenza virus, can infect and also cause morbidity in lung transplant recipients. Because CRV and OB/BOS affect the small airways, we sought to determine whether CRV infections predisposed patients to OB/BOS. METHODS: To determine whether CRV predisposed to OB/BOS, a proportional hazards regression analysis of time to OB/BOS was performed with CRV as a time-dependent covariate. To determine the influence of OB/BOS on the subsequent development of CRV infection, we reversed the outcome and time-dependent covariate. To illustrate the effect of CRV on OB/BOS and the effect of OB/BOS on CRV, landmark plots were generated at specific time points. Time to development of OB/BOS was then compared using the Kaplan-Meier method. RESULTS: In our institution, we documented 40 infections caused by CRV in 33 lung transplant recipients during an 11-year period. Community respiratory virus infections occurred predominantly during seasonal community outbreaks, except for parainfluenza infections, which occurred throughout the year. The diagnosis of OB/BOS occurred throughout the year and was not associated with seasonal outbreaks of CRV. Community respiratory virus infection involving both upper and lower respiratory tracts did not predispose to OB or BOS (relative risk [RR], 1.1; 95% confidence interval [CI], 0.52-2.3; p = 0.81). However, patients with documented CRV infection of the lower respiratory tract were predisposed to high-grade BOS development (RR, 2.3; 95% CI, 1.1-4.9; p = 0.04). In addition, a patient with pre-existing OB or BOS was predisposed to developing both upper and lower respiratory tract infection with CRV (RR, 4.2; 95% CI, 1.9-9.4; p < 0.001). CONCLUSIONS: Patients with CRV infection of the lower respiratory tract were predisposed to high-grade BOS development, and patients with OB and BOS were predisposed to CRV infections.     

Development of an antibody specific to major histocompatibility antigens detectable by flow cytometry after lung transplant is associated with bronchiolitis obliterans syndrome

BACKGROUND: Chronic allograft rejection manifested as bronchiolitis obliterans syndrome (BOS) is the leading cause of late death after lung transplantation. Although increasing evidence suggests an association between anti-human leukocyte antigens (HLA) antibodies and chronic rejection of kidney or heart allografts, the clinical significance of anti-HLA antibodies in lung recipients is less clear, especially in previously unsensitized recipients. The use of flow cytometry based panel reactive antibody (flow-PRA) provides a highly sensitive means to identify the development of de novo anti-HLA antibodies in lung recipients. METHODS: Flow-PRA testing was used to analyze the pre- and posttransplant sera in stable BOS free lung recipients who survived at least 6 months. Patients without prior sensitization as defined by a negative pretransplant flow-PRA were analyzed posttransplant for the presence of anti-HLA antibodies by flow-PRA. A proportional hazards model was used to determine the impact of anti-HLA antibody on BOS risk. RESULTS: Sera from 90 recipients at Duke University with negative pretransplant flow-PRA were tested by flow-PRA at various time points after transplant. Sera from 11% (10/90) of recipients were found to contain anti-HLA antibodies detectable by flow-PRA. Nine patients (90%) developed anti-HLA antibodies specific for donor antigens, and one patient developed anti-HLA class II antibodies, not specific to donor antigens. Among the nine patients with donor antigen specific antibodies, flow-PRA specificity analysis demonstrated eight were specific for class II antigens and one for class I antigens. In a multivariate model that controls for other BOS risk factors, a positive posttransplant flow-PRA was significantly associated with BOS grades 1,2, or 3 (hazard ratios [HR] 3.19; 95% confidence interval [CI]: 1.41-7.12, P=0.005) and BOS grade 2 or 3 (HR 4.08; 95% CI: 1.66-10.04, P=0.002). Four patients with de novo anti-HLA antibodies died during follow-up; all four had BOS. Among BOS patients, the presence of anti-HLA antibodies was associated with a significantly worse survival (P =0.05, log-rank test). CONCLUSIONS: Although uncommon, previously unsensitized lung transplant recipients can develop anti-HLA antibodies to donor class II antigens. The development of de novo anti-HLA antibodies significantly increases the risk for BOS, independent of other posttransplant events. Furthermore, de novo anti-HLA antibodies identify BOS patients with significantly worse survival. Additional studies are needed to determine if class II-directed anti-HLA antibodies contribute mechanistically to the chronic rejection process in lung recipients.     

Impact of early cytomegalovirus infection and disease on long-term recipient and kidney graft survival

BACKGROUND: The impact of cytomegalovirus (CMV) infection and disease on long-term outcome after kidney transplantation is still unsettled. METHODS: Between 1994 and 1997, 397 consecutive first kidney graft recipients and 74 retransplants were included in the study and followed prospectively until December 31, 2001. CMV infection (CMV pp65 antigenemia) and CMV disease were recorded once weekly during the first 100 days after transplantation. No CMV prophylaxis or preemptive therapy was given. In a multiple Cox proportional hazard model allowing time-dependent covariates, the effects of asymptomatic CMV infection and CMV disease, recipient age and gender, retransplantation, living donor, panel-reactive cytotoxid antibodies, acute rejection, and graft loss were tested on overall mortality beyond 100 days post-transplantation. In a similar analysis, the effect of asymptomatic CMV infection and CMV disease plus other factors were tested on death censored graft loss beyond 100 days. RESULTS: Median (range) follow up time was 66.6 (<1-86.9) months. The incidence of CMV infection and disease during the first 100 days was 62.8% and 23.4%, respectively. The number of total deaths was 96 (20%), 82 occurred after the first 100 days. Independent risk factors for overall mortality beyond 100 days were asymptomatic CMV infection, RR = 2.90 (95% CI 1.61-5.22) (P= 0.001), CMV disease, RR = 2.50 (95% CI 1.31-4.79) (P= 0.006), both compared to no infection or disease, recipient age, RR = 1.066 per year (95% CI 1.048-1.084) (P < 0.001), and graft loss in the whole study period RR = 7.88 (95% CI 4.75-13.08) (P < 0.001). Asymptomatic CMV infection and CMV disease were not independent risk factors for death censored graft loss, but they significantly reduced graft survival uncensored for death, (log rank P= 0.001, respectively). CONCLUSION: Asymptomatic CMV infection and overt CMV disease during the first 100 days increase the risk of recipient mortality beyond 100 days. This raises the question whether CMV prophylaxis should be given routinely after kidney transplantation.     

The influence of histocompatibility on graft rejection and graft survival within a single center population of heart transplant recipients.

BACKGROUND: We report a consecutive single center series of 261 patients who received first orthotopic heart transplants from 1986 to 1997. The 1- and 5-year graft survivals were 78 and 68%. The influence of histocompatibility was investigated by comparing graft survival and numbers of treated rejection episodes with HLA-A, -B, and -DR mismatches over different time periods. FINDINGS: Recipients with six mismatches for HLA-A+-B+-DR combined (13.4%) had reduced survival at 7 years (47%) when compared with other recipients (64%). In the first year of transplant, recipients with four HLA-A+-B mismatches had significantly reduced actuarial graft survival (P=0.03) with the greatest influence apparent at 6 months [0-3 mismatches (n=193) 85% versus 4 mismatches (n=68) 69%; P=0.005, OR=2.1]. For 182 recipients with functioning hearts at 1 year, the number of rejection episodes treated within this time was strongly influenced by HLA-DR mismatch [0 DR mismatch (n=15) mean 1.2 rejection episodes versus 1 DR mismatch (n=76) mean 2.7 rejection episodes versus 2 DR mismatches (n=91) mean 3.8 rejection episodes: P=0.0002]. Of these 182 transplants, recipients who had more than four treated rejection episodes during the first year had a significantly reduced 7- year survival [<5 rejection episodes (n=133) 85% versus more than four rejection episodes (n=49) 66%; P=0.02, OR=3.4], as did those with two HLA-DR mismatches [0+1 mismatch (n=91) 87% versus 2 mismatches (n=91) 70%; P<0.05, OR=2.4]. INTERPRETATION: We show that graft loss in the first 6 months of transplant is significantly influenced by four HLA-A+-B mismatches. HLA-DR mismatch significantly increases the number of rejection episodes within the first year, without influencing graft survival. After 12 months both >4 rejection episodes in the first year and two HLA-DR mismatches are markers for late graft loss. We postulate that immunological graft loss in the first 6 months is dominated by the direct allorecognition pathway driven by HLA-DR mismatch. This mechanism is later lost or suppressed. Our data highlight HLA-DR mismatch as a marker for late graft loss and we show an advantage to avoiding transplanting hearts with six HLA-A+-B+-DR mismatches and to minimizing HLA-DR mismatches whenever possible.     

Influence of mismatching of HLA cross-reactive groups on cadaveric kidney transplantation

Finding fully HLA-matched recipients for a given donor is not practical due to the allelic diversity of the loci. Cross-reactive group (CREG) matching has been considered a feasible alternative to HLA matching. However, the true efficacy of CREG matching in cadaveric kidney transplantation is controversial. Using conventional HLA and CREG classifications proposed by Rodey and McKenna, we counted the number of mismatches for 319 patients who received cadaver kidney transplants between 1992 and 2003 at Asan Medical Center in Korea. When we compared transplants with four or fewer HLA-A, -B, and -DR antigen mismatches with those with five or more, we observed a significant difference in 5-year survival rate (88.5% versus 78.6%; P = .0189). Transplants with no or one HLA-DR mismatch had a significantly better 5-year survival rate than those with two HLA-DR mismatches (87.9% versus 80.0%; P = .0469). Among transplants with one or two HLA-DR mismatches, transplants with zero or one CREG mismatch showed better 5-year graft survival rate than those with two or more CREG mismatches (89.4% versus 79.8%; P = .0415) only in McKenna's CREG classification. These results suggest that the impact of CREG mismatches on graft survival may depend on CREG classification and on the distribution of HLA-DR mismatches.     

Correlation of HLA matching with kidney graft survival in patients with or without cyclosporine treatment

In a series of more than 8000 first cadaver transplants performed during a two-year period, 2198 recipients treated with cyclosporine had a higher graft survival rate (76 +/- 1% at 1 year) than 6392 recipients without cyclosporine (64 +/- 1%, P less than 0.0001). Matching for HLA-B plus HLA-DR resulted in a significant correlation with graft outcome, in patients with or without cyclosporine treatment (P less than 0.0001). Regardless of whether cyclosporine was used or not, grafts with 0 HLA-B,-DR incompatibilities had approximately 20% higher success rates at one year than grafts with 4 mismatches. A high (86 +/- 3%) graft survival rate was obtained in 161 cyclosporine-treated recipients with 0 HLA-B,-DR mismatches. Matching for the HLA-B and HLA-DR loci is shown to have an additive effect in cadaver kidney transplantation.     

Cytomegalovirus viremia associated with death or retransplantation in pediatric lung-transplant recipients

BACKGROUND: Cytomegalovirus (CMV) infection is a frequent complication of lung transplantation. However, there is limited information regarding the incidence and sequelae of CMV infections in pediatric lung-transplant recipients. On the basis of case series suggesting that CMV infection was associated with excess morbidity and mortality in lung-transplant recipients, we hypothesize that CMV viremia increases the risk of bronchiolitis obliterans (BOS) or death and retransplantation in the first year following transplantation. METHODS: A case-cohort study of pediatric primary lung-transplant recipients was performed. Univariate analysis was used to assess whether CMV viremia was associated with BOS or death and retransplantation within 1 year after transplantation. Patients at high risk for CMV infection received ganciclovir prophylaxis for 42 days posttransplantation. RESULTS: From July 1990 to November 2000, 194 pediatric patients received primary lung transplants. Twenty-three percent of patients developed CMV viremia. Eighty percent of CMV viremia episodes occurred before 120 days posttransplant. A first episode of CMV viremia was associated with retransplantation or death between days 90 and 365 (RR=4.1, 95% confidence interval [CI] 1.1-14.5) and was not associated with BOS (RR=1.3, 95% CI 0.5-3.3). CONCLUSIONS: CMV viremia in the first year after pediatric primary lung transplantation is associated with increased risk of death or retransplantation between 90 and 365 days posttransplant, when CMV prophylaxis has stopped. A phase II pilot trial is warranted to assess safety and short-term efficacy of increasing the duration of CMV prophylaxis from 42 to 120 days.     

Indirect Allorecognition of Mismatched Donor HLA Class II Peptides in Lung Transplant Recipients with Bronchiolitis Obliterans Syndrome

A correlation between indirect allorecognition of mismatched donor HLA class I peptides and development of bronchiolitis obliterans syndrome (BOS) after lung transplantation has been previously observed. The aim of this study was to determine whether there was a correlation between indirect allorecognition of mismatched donor HLA class II peptides and development of BOS after lung transplantation. Peripheral blood mononuclear cells from nine BOS+ and nine BOS-lung transplant recipients were cultured with synthetic peptides corresponding to the beta-chain hypervariable region of a mismatched donor HLA-DR molecule. Then, proliferative alloreactivity as well as frequency of alloreactive T cells were determined. In addition, the immunodominant epitopes from the donor HLA-DR molecules were identified in selected patients. T cells from BOS+ patients showed a dose-dependent proliferative alloreactivity against donor HLA-DR peptides that was significantly higher than that observed in BOS- patients (p=0.001). Similarly, the frequency of HLA-DR alloreactive T cells was significantly higher in BOS+ patients than in BOS- patients (p=0.001). This T-cell alloreactivity was directed against a single immunodominant HLA-DR peptide. These results suggest that indirect alloreactivity to donor HLA class II molecules may play a role in the pathogenesis of BOS after lung transplantation.     

Multivariate analysis of donor risk factors for graft survival in kidney transplantation

BACKGROUND: The results of the transplantation of marginal donor kidneys remain controversial. This study aimed to investigate the impact of donor risk factors as predictors of kidney-graft outcome. METHODS: Allograft failure risk factors were studied in 7,209 cadaveric kidney-transplant recipients reporting to the Etablissement fran?ais des Greffes (EfG) from 1996 to 2000, of which 544 (7.6%) were from donors aged over 60. Both univariate and multivariate analysis were used to assess the effect of donor risk factors and were stratified according to recipient age. RESULTS: Overall graft survival was 91.1% (95% confidence interval [CI] 90.5-91.8) at 1 year, 88.6% (95% CI 87.8-89.4) at 2 years, and 85.6% (95% CI 84.6-86.6) at 3 years posttransplant. Univariate analysis of risk factors showed a significant reduction of graft survival in recipients transplanted with kidneys coming from donors older than 60 years, donors with a history of hypertension, a cerebrovascular cause of death, and a preharvesting serum creatinine greater than 150 micromol/L. Multivariate analysis revealed significantly higher failure rate associated with cerebrovascular cause of death (RR=1.2, P=0.02), history of hypertension (RR=1.2, P=0.04), and elevated serum creatinine (RR=1.3, P=0.03), whereas donor age greater than 60 years was not found as an independent risk factor. CONCLUSIONS: Our results suggest that cerebrovascular cause of death, history of hypertension, and elevated creatinine are significant independent donor risk factors for graft survival, whereas donor age is a statistically significant, but dependent, risk factor. This result is important for the design of allocation and transplantation strategies for kidneys procured in elderly donors.     

Kidney graft survival in Italy and factors influencing it

PURPOSE: National registry data are often a suitable basis for examination of transplant outcomes. Using data supplied by the Italian National Transplant Registry, established in 1995, we performed the first nationwide analysis of this kind. METHODS: A retrospective analysis of 4893 recipients of cadaveric kidneys transplanted in all Italian centers from 1995 through 2000 was done to study 5-year graft survival. The association between some donor and recipient variables and outcomes in renal transplantation was analyzed. Graft survival was 93% at 3 months, 89% at 1 year, 82% at 3 years, and 80% at 5 years after transplantation. RESULTS: A significant association between graft survival and donor age (old vs young, relative risk [RR] = 1.62, 95% CI 1.27-2.06) and recipient age (old vs young, RR = 1.25, 95% CI 1.02-1.53). Graft survival was also associated with cold ischemia time (24-36 hours, RR= 1.39, 95% CI 1.05-1.85 and >36 hours, RR= 1.94, 95% CI 1.32-2.86 vs 0-24 hours) and donor/recipient sex mismatch (female/male vs male/male, RR= 1.50, 95% CI 1.17-1.93). CONCLUSION: The quality of kidney transplantation in Italy is satisfactory and is comparable to that in other developed countries. Furthermore, our experience confirms that both donor and recipient factors are major determinants of renal allograft function.     

Renal transplantation in patients with hemolytic uremic syndrome: high rate of recurrence and increased incidence of acute rejections

BACKGROUND: The reported outcome of renal transplantation in patients with the hemolytic uremic syndrome (HUS) varies greatly, probably related to the diverse causes of HUS. In this single-center retrospective study, we have analyzed the recurrence rate, the incidence of acute rejections, and graft survival in patients suffering from adult-onset and childhood-onset HUS. METHODS: The medical records of 35 patients with end-stage renal disease caused by HUS, who received 50 renal allografts, were reviewed. A definite recurrence of HUS was diagnosed if both clinical and histologic signs of thrombotic microangiopathy (TMA) were present in the absence of any endovasculitis. If there were signs of mild endovasculitis, a probable recurrence was diagnosed. RESULTS: After first renal transplantation, 0 definite and 1 (6%) probable recurrence occurred in 18 patients with childhood-onset HUS, as opposed to 7 (41%) definite and 3 (18%) probable recurrences in 17 adult-onset HUS patients (odds ratio [OR], 13.4; 95% confidence interval [CI], 1.7-105.7). In the latter patients, early use of cyclosporine A increased the risk for recurrence. The incidence of acute rejections was increased compared with matched controls (OR, 1.52; 95% CI, 1.05-2.19 for adult-onset HUS and OR, 1.88; 95% CI, 1.34-2.62 for childhood-onset HUS). One-year graft survival in adult-onset HUS was poor (29%), whereas 1-year graft survival in childhood-onset HUS was comparable to matched controls. CONCLUSIONS: In adult-onset HUS, the recurrence rate and the incidence of acute rejections are high, resulting in a detrimental graft survival. In childhood-onset HUS, the recurrence rate is low, but the posttransplantation course is complicated by an increased incidence of acute rejections.     

An analysis of pretransplantation variables associated with long-term allograft outcome in pediatric liver transplant recipients receiving primary tacrolimus (FK506) therapy.

BACKGROUND: The present study analyzes pretransplantation variables associated with long-term liver allograft survival in 278 children who underwent transplantation under primary tacrolimus (FK506) therapy at a single center between October 1989 and October 1996. METHODS: The influence of 17 pretransplantation variables on long-term liver allograft outcome was analyzed. Donor variables included age, weight, gender, and cold ischemia time. Recipient variables included age, weight, gender, original liver disease, pretransplantation waiting time, previous abdominal surgery, United Network of Organ Sharing (UNOS) status, ABO blood group, bilirubin level, prothrombin time, ammonia level, creatinine level, and reduced-size/split liver grafts. RESULTS: Overall actuarial graft survival was 79.9% at 1 year, 79.1% at 2 years, and 78.3% at 3, 4, and 5 years. Retransplantation rate was 10.8%. Pretransplantation variables with a significant adverse effect on graft survival by univariate analysis were donor age < or = 1 year (P<0.004), donor weight < or = 10 kg (P<0.003), UNOS status I and II (P<0.007), ABO type O, B, and AB (P<0.03), and reduced-size/split liver grafts (P<0.02). Pretransplantation variables significant by multivariate analysis and therefore independent predictors of inferior graft outcome were donor weight '10 kg (relative risk [RR] 2.91, confidence interval [CI] 1.53-5.51); reduced-size/split liver grafts (RR 2.53, CI 1.30-5.64); and UNOS status I (RR 2.22, CI 1.11-4.43). CONCLUSIONS: Pediatric liver transplant recipients receiving primary tacrolimus therapy have long-term graft survival rates approaching 80%. UNOS status, donor weight, and the use of reduced-size/split liver grafts are the most important factors affecting survival.     

Long-term effect of hepatitis C virus chronic infection on patient and renal graft survival

BACKGROUND: Hepatitis C virus (HCV) infection increases morbimortality in renal transplantation. The immune response against the HVC is not predictable in a great proportion of patients developing into chronic liver disease, glomerulonephritis, or both. PATIENTS: We analyzed the impact of posttransplant chronic hepatitis development on patient and graft survival in 200 HCV-positive/HBsAg-negative renal allograft recipients transplanted between 1981 and 2003. RESULTS: Ninety-eight patients developed chronic ALT elevation (ALT+), while 102 did not (ALT-). There was no difference in acute rejection episodes (ARE), acute tubular necrosis, donor and recipient age, gender, HLA mismatches, and number of previous renal transplants. Development of ALT+ was associated with a worse patient survival (90% vs 65% at 15 years of follow-up, P = .007; RR = 3.8, CI = 1.4-10.1), an effect that was independent of other variables as time on dialysis and age. The main causes of death among ALT+ were chronic liver disease (52%), cardiovascular (26%), and infection (13%), whereas in ALT- they were cardiovascular (33%), cancer (33%), and chronic liver disease (16%). Conversely, graft survival (censoring for patient death with a functioning graft) was higher among ALT+ (50% vs 35% at 15 years of follow-up, P = .04; RR = 1.5, CI = 1.19-2.22). Causes of graft loss in ALT- patients were chronic allograft nephropathy (CAN, 53%), glomerulonephritis (GN, 18%), acute rejection episode (AR, 22%), and death (5%), whereas among ALT+ they were CAN (36%), GN (31%), ARE (10%), and death (21%; P = .01). By multivariate analysis, ALT- (RR = 1.6, CI = 1.07-2.55, P = .02) and de novo GN (RR = 2, CI = 1.29-3.09, P = .002) were associated with worse renal allograft survival. CONCLUSION: Our results suggested that a better immune response against the HCV lead to greater patient survival but poorer graft survival.     

Relationship between donor factors, immunogenic up-regulation, and outcome after kidney transplantation

Epidemiological data show that the cause of brain death as well as the condition of the organ donor have considerable influence on the outcome of kidney transplantation. An early immunogenic up-regulation, which already exists at the time of organ removal seems to be primarily responsible. So far it has remained unclear which donor factors cause this effect. In a prospective study of 37 organ donors a 0-hour biopsy was performed at the time of explantation to measure the expression of HLA-DR and endothelin-1 (ET-1) immunohistologically using the alkaline phosphatase anti-alkaline phosphatase (APAAP) method. The transplant outcome and the immunohistological results were correlated with various donor factors. Statistically significant correlations were seen with the following parameters: the donor serum creatinine prior to explantation correlated with the incidence of delayed graft function (DGF: 104 +/- 39 vs 78 +/- 35 micromol/L versus no DGF n = 37; P = .043). Early graft loss after transplantation correlated significantly with increased numbers of leukocytes as well as with decreased O2 saturation in the donor immediately before explantation (leucocytes: 16.7 +/- 6.8 vs 12.6 +/- 4.6/nL, n = 37; P = .036; O2 saturation: 94.1% +/- 6.9%, vs 97.7% +/- 2.3%, n = 37; P = .026). Further, donor-independent factors that correlated with acute rejections included cold ischemic time (P = .031), HLA mismatches (P = .028), and occurrence of DGF (P = .033). The degree of HLA-DR expression (range 0 to 2) correlated significantly with early graft loss (2.0 +/- 0.2 vs 1.33 +/- 0.9 for graft function, n = 37; P = .01) as well as the ET-1 expression with DGF (2.0 +/- 0.3 vs 1.5 +/- 0.7 versus no DGF, n = 37; P = .016). In summary, marginal donors should be seen as high immunological risk situations that need careful conditioning.     

Immunosuppression with calcineurin inhibitors with respect to the outcome of HCV recurrence after liver transplantation: results of a meta-analysis.

A controversy exists over whether the outcome of a hepatitis C virus (HCV)-infection-related liver transplant differs based on the calcineurin inhibitor (CNI) used. We have performed a systematic review and a subsequent meta-analysis evaluating tacrolimus (Tac)-based vs. cyclosporine A-based immunosuppression in HCV-infected liver transplant recipients. Searches were conducted to locate randomized controlled trials comparing Tac vs. cyclosporine A. Data on HCV liver transplant recipients were obtained, independently of whether the study was specifically designed for patients with this disease or not. A fixed effects model was used for statistical pooling of the relative risks (RR) for the different outcomes. A total of 5 articles (366 patients) fulfilled the inclusion criteria. Statistically significant differences between Tac-based vs. cyclosporine A-based therapies were not found for mortality (P = 0.11; RR = 0.72; 95% confidence interval [CI], 0.49-1.08), graft survival (P = 0.37; RR = 0.86; 95% CI, 0.61-1.21), biopsy-proven acute rejection (P = 0.65; RR = 0.91; 95% CI, 0.61-1.36), corticoresistant acute rejection (P = 0.26; RR = 2.25; 95% CI, 0.55-9.29), and fibrosing cholestatic hepatitis (P = 0.92; RR = 0.96; 95% CI, 0.41-2.26). In 1 study, no differences were detected regarding severe fibrosis at 1 yr. In conclusion, patient and graft survivals in HCV-positive liver transplant patients are similar independently of the CNI selected as basic immunosuppressant. Unfortunately, data on the severity of recurrence and effect on viremia are scarce. Well-designed randomized prospective studies are needed to determine whether there are differences between the 2 CNIs regarding these specific variables.     

Evaluation of pre- and posttransplant donor-specific transfusion/cyclosporine A in non-HLA identical living donor kidney transplant recipients. Cooperative Clinical Trials in Transplantation Research Group.

BACKGROUND: The beneficial effects of donor specific transfusion (DST) have become controversial in the cyclosporine era. This study was performed to evaluate the potential benefits of a new protocol for administering DSTs in the perioperative period. METHODS: Non-HLA identical living donor kidney transplant recipients were randomized prospectively to control or to receive a DST 24 hr before transplant and 7-10 days posttransplant. All patients received similar immunosuppression according to protocol. RESULTS: The protocol had 212 evaluable patients (115 transfused and 97 control). There were no differences in 1- and 2-year graft and patient survival, causes of graft failure, incidence and types of infection, repeat hospitalization, or the ability to withdraw steroids. Immunological hyporesponsiveness (by mixed lymphocyte culture) occurred more frequently in transfused patients (18%) than controls (3%) (P = 0.04). Blood stored for > or =3 days was associated with fewer early rejections than blood stored < or =2 days. Overall, class II antigen mismatches were associated with more rejection episodes than class I antigen mismatches. However, transfused patients, but not control patients, with more class I antigen mismatches were more likely to have rejections. CONCLUSIONS: Administration of DSTs by the method described had no practical influence on patient or graft survival for up to 2 years. However, donor-specific hyporesponsiveness was more common in transfused patients (18 vs. 3%). Longer follow-up will be needed to determine whether DST will be associated with long-term benefit.