Cytomegalovirus antibody status of donor/recipient does not influence the incidence of bronchiolitis obliterans syndrome in lung transplantation.

BACKGROUND: We have previously reported that prophylaxis for cytomegalovirus (CMV) infection does not influence the incidence of bronchiolitis obliterans syndrome (BOS) at 2 years. The effect of CMV infection (without evidence of disease) on BOS is still not well understood. Moreover, the incidence and risk factors for development of BOS in CMV-antibody-negative donor/recipient matches in lung transplantation have not been described. The aim of this study is to determine the incidence of BOS in lung transplant patients with CMV-antibody-negative (-) donors (D) and recipients (R), and to evaluate the risk factors that predispose to BOS in this sub-group. METHOD: A retrospective study of data from the transplant database of our center was performed. All single-lung (SL), double-lung (DL) and heart-lung block (HL) transplant patients who survived >2 years post-transplant were included in the study group. They were grouped as follows: D(-)/R(-), n = 102; D(-)/R(+), n = 70; D(+)/R(-), n = 33, and D(+)/R(+), n = 92. RESULTS: The 3-year BOS-free survival rates were 65%, 56%, 58% and 67%, respectively, and the incidence rates of BOS at 5 years post-transplant in the different groups were 57%, 62%, 78% and 55% (p > 0.05). In the D(-)/R(-) group, the significant risk factor for developing BOS was three or more episodes of acute rejection (p = 0.02). The mean numbers of acute rejection episodes per 100 patients-days within the first 6 months were 1.28, 1.06, 0.50 and 1.11 (p < 0.001 overall) for the four groups, respectively. CONCLUSION: Although CMV is believed to be a risk factor for BOS, its absence did not affect the occurrence or incidence of BOS in lung transplant patients. The main risk factor for BOS in the CMV-antibody-negative population remains the number of acute rejection episodes within the first 6 months after transplantation.     

The Eurotransplant Study on Twin Lung Transplants (ESOTWIN): 90 paired single-lung transplants from the same donor

BACKGROUND: Despite its reduced benefit for a single recipient, the transplantation of two single-lung allografts as opposed to one bilateral lung transplant has the indisputable advantage of maximizing the number of patients that benefit from a single donor. METHODS: In the period 1997 to 1999, 90 paired single-lung transplants (SLTx) from 45 donors were performed in 16 lung centers in Eurotransplant, with a complete follow-up of 1 year. RESULTS: No significant differences between left- and right-lung allograft recipients were observed regarding age, sex, primary disease, number of human leukocyte antigen mismatches, cold ischemic time, and donor-to-recipient cytomegalovirus match. Early posttransplant outcome, as assessed by oxygenation index at 12, 24, and 48 hr, also did not differ significantly, and there were no differences in time to extubation and time spent in the intensive care unit. In the first month, six left- and three right-lung allograft recipients died. Bronchiolitis obliterans syndrome developed in 5 of 39 left-lung and 10 of 42 right-lung allograft recipients. If the retrieval team was different from the transplanting team, a significantly worse 1-year posttransplant survival rate was seen in patients who underwent left SLTx compared with those who underwent right SLTx (62% vs. 92%, respectively; P=0.04). CONCLUSIONS: More fatal posttransplant complications occur in patients undergoing left SLTx compared with right SLTx. A less optimistic assessment of the left lung by the not-implanting retrieval team is warranted.     

Comparison of mycophenolate mofetil and azathioprine for prevention of bronchiolitis obliterans syndrome in de novo lung transplant recipients

BACKGROUND: There are no data on the effects of mycophenolate mofetil (MMF) on the incidence of bronchiolitis obliterans syndrome (BOS) in lung-transplant patients. This study attempted to determine whether MMF reduces the incidence of BOS in de novo lung transplant recipients compared with azathioprine (AZA). METHODS: This prospective, randomized, open-label, multicenter study compared the effects of MMF with AZA in combination with induction therapy, cyclosporine (Neoral) and corticosteroids in patients receiving their first lung transplant. Primary endpoint was incidence of BOS at 3 years. Secondary endpoints were incidence of acute rejection, time to first rejection event, and survival. RESULTS: The incidence of acute rejection and the time to first rejection event at 1 and 3 years did not differ between groups (54.1% vs. 53.8% and 56.6% vs. 60.3% for MMF and AZA respectively). Survival at 1 year tended to be better in patients receiving MMF (88 vs. 80%, P = 0.07). At year 3, there was no difference in survival or in the incidence, severity or time to acquisition of BOS between the two groups. Treatment was generally well tolerated, however more patients withdrew from AZA treatment than from MMF (59.6% vs. 46.5%, P = 0.02). As a result, there was an imbalance in the observation times of the two groups (876 +/- 395 vs. 947 +/- 326 days). CONCLUSIONS: No differences were seen in the incidence of acute rejection or BOS in lung transplant recipients treated with MMF or AZA. This null result may have been influenced by the shorter observation time for AZA patients.     

Lung transplantation: a decade of experience.

BACKGROUND: Over the past 3 decades, the field of lung transplantation has been refined. However, many barriers exist that limit long-term success. The purpose of this study was to review a single institution's long-term experience with single and double lung transplantation and to assess the effect of different immunosuppressive therapies on outcomes. METHODS: Lung transplant recipients, both single and double, were reviewed, retrospectively. Patients were divided into five groups: group I, all lung transplants (n = 127); group II, single lung transplants (n = 73); group III, double lung transplants (n = 54); group IV, OKT3 induction therapy recipients (n = 27); and group V, RATG induction therapy recipients (n = 100). Rates of survival, rejection, bronchiolitis obliterans syndrome (BOS) and infection were analyzed at 1, 3, and 5 years. RESULTS: There were no significant differences in survival, acute rejection rate, freedom from BOS, nor infection between single and double lung transplant recipients. Induction therapy with RATG (group V) was associated with significantly improved survival and freedom from acute rejection, BOS, and infection when compared to OKT3 induction therapy (group IV). CONCLUSIONS: An earlier impression that RATG is superior to OKT3 induction therapy has borne true in terms of overall survival and incidence of BOS, acute rejection and infection rates. Lung transplantation, using RATG induction therapy, remains an important modality for end-stage pulmonary disease.     

Inflammation Patterns in Allogeneic and Autologous Airway Tissue of Lung Transplant Recipients

Inflammatory injuries directed toward airway structures play a key role in lung allograft rejection. However, data relating to the inflammation patterns of large airways are scarce and, in particular, the relation between autologous and allogeneic parts is unknown. For the first time, in this study, simultaneously collected endobronchial biopsies from the main (autologous) and upper lobe (allogeneic) carina of lung transplant recipients were assessed immunohistologically. A total of 27 pairs of EBBs were taken. Twelve endoscopies documented acute rejection and four examinations of patients with BOS were performed. Patients with acute rejection had more CD8-positive cells in the allogeneic parts compared with patients without acute rejection. Patients with BOS had more CD4- and CD45-positive cells in the autologous airways than stable patients. We conclude that distinct inflammatory changes do occur in large airways of lung transplant recipients and are not limited to the donor parts of airways.     

Similarity of pulmonary rejection patterns among heart-lung and double-lung transplant recipients

The transbronchial biopsy and clinical courses of 9 double-lung and 1 single-lung recipients surviving greater than 10 days were analyzed and compared to those of 15 heart-lung transplants performed during the same time period. Of these, 8 isolated lung (LT) and 11 heart-lung transplant (HLT) recipients survived greater than 50 days and were at risk of developing obliterative bronchiolitis believed to be a form of chronic rejection. Cyclosporine-based immunosuppression, in combination with azathioprine and steroids, was used for 22 of 25 patients. Two double-lung recipients and 1 heart-lung patient received FK506 as the sole immunosuppressive agent; 90% and 62% of LT, and 67% and 54% of HLT recipients developed acute and chronic rejection, respectively (P = NS). The average time to first episode of acute (30.2 days [LT] versus 21.5 days [HLT]) and chronic rejection (146 days [LT] versus 193.7 days [HLT]) was not different between groups (P = NS). Age (34.2 [LT] versus 29.1 [HLT]) and sex (M:F, 5:5 [LT] versus 5:10 [HLT]) were also not found to be discriminators. The histologic diagnosis of chronic rejection was associated with significant declines in FEV1.0 and FEF25-75 (P less than 0.02). There was only one instance of cardiac rejection among the heart-lung transplant recipients. Heart-lung and isolated lung transplant patients appear to be at similar risk for developing acute or chronic pulmonary rejection.     

Comparative study of basiliximab treatment in lung transplantation

OBJECTIVE: This study compared the incidence of acute or chronic rejection and adverse events in lung transplant patients receiving induction basiliximab versus controls not receiving treatment. MATERIALS AND METHODS: Basiliximab was administered to 15 patients with impaired renal function, advanced age, or high surgical risk, (group I). The mean age was 48.9 years; nine were double-lung and six single-lung grafts. They were compared to 13 lung transplants performed in 2001 (mean age 43.6 years, 11 double lung and two single lung [group II]). RESULTS: The incidence of acute rejection was 13.3% in group I versus 38.5% in group II (P = .19, OR 4.06), with chronic rejection in 20% and 38.5% of cases, respectively (P = .4, OR 2.5). No significant differences were observed in the incidence of infections or malignancies. Nor were there any direct adverse events due to the administration of the drug. The estimated 2-year survival was 80% for group I and 54% for group II (P = .14). CONCLUSIONS: Basiliximab has a trend to reduce the rate of acute and chronic rejection in lung transplant recipients, with no increased incidence of infections or malignancies. The 2-year survival for patients treated with basiliximab was better than the control group, despite including high risk transplant patients.     

Immunobiology of Chronic Lung Allograft Dysfunction: New Insights from the Bench and Beyond

The first successful human lung transplants were performed in the 1980s. Since that time lung transplantation has been a therapeutic modality for end-stage pulmonary diseases. However, chronic rejection, known as obliterative bronchiolitis (OB)/bronchiolitis obliterans syndrome (BOS), is the key reason why the 5-year survival is only 50%, which is significantly worse than most other solid organ transplants. Recent studies have provided exciting advances that are beginning to be translated into findings in humans. This review will highlight the current advances in understanding the mechanisms of OB/BOS in lung transplant recipients.     

Bacterial colonization of the donor lower airways is a predictor of poor outcome in lung transplantation.

OBJECTIVE: At the time of lung transplant, we routinely perform bronchoalveolar lavage (BAL) of the donor lungs on the recipient operating table immediately before implantation, for bacterial and fungal cultures. We sought to determine whether the results correlate with the outcome. METHODS: We retrospectively analysed 115 consecutive cadaveric lung transplants (single lung: 42; bilateral lung: 63; heart-lung: 10) performed over 4 years. RESULTS: Fifty-three (46%) grafts had positive BAL (bacteria: 33; fungus: 10; mixed: 10) and 62 (54%) were negative. Recipients with donor BAL culture positive for bacteria had lower mean oxygenation index in the first 6 h compared with those with negative bacterial culture (36.5+/-14.73 vs. 44.1+/-16.79 kPa) (P=0.019). They also had longer median intensive treatment unit stay (2.5 vs. 1.5 days) (P=0.035), and median time of mechanical ventilation (37.5 vs. 23.0 h) (P=0.008), as well as inferior 6-month, 1-year, 2-year and 4-year cumulative survival (79, 77, 74, 60% vs. 93, 92, 88, 79% respectively) (P=0.04). There was no difference in the above parameters between recipients with Gram-negative (n=18) and recipients with Gram-positive bacteria (n=19) in the donor BAL. Incidence of acute rejection within the first 2 weeks and time of onset of bronchiolitis obliterans syndrome (BOS) were similar in the bacteria-positive and bacteria-negative groups. Recipients with donor BAL positive for fungi alone had similar outcome with the negatives. There was no difference in the donor oxygenation index and age, recipient age, transplant type and ischaemic time between compared groups. There was a significant difference in the median length of donor mechanical ventilation between donors with Gram-positive and donors with Gram-negative bacteria in the BAL (24 vs. 48 h) (P=0.01), as well as between donors with fungi alone in the BAL and donors with negative BAL (67 vs. 48 h) (P=0.04). CONCLUSIONS: Donor lungs with lower airways colonized with bacteria result in inferior recipient outcome. Bacterial colonization of the donor lower airways could therefore be used as a marker of donor lung injury, but evidence from a prospective study is necessary.     

Aspergillus Colonization of the Lung Allograft Is a Risk Factor for Bronchiolitis Obliterans Syndrome

Multiple infections have been linked with the development of bronchiolitis obliterans syndrome (BOS) post-lung transplantation. Lung allograft airway colonization by Aspergillus species is common among lung transplant recipients. We hypothesized that Aspergillus colonization may promote the development of BOS and may decrease survival post-lung transplantation. We reviewed all lung transplant recipients transplanted in our center between January 2000 and June 2006. Bronchoscopy was performed according to a surveillance protocol and when clinically indicated. Aspergillus colonization was defined as a positive culture from bronchoalveolar lavage or two sputum cultures positive for the same Aspergillus species, in the absence of invasive pulmonary Aspergillosis. We found that Aspergillus colonization was strongly associated with BOS and BOS related mortality in Cox regression analyses. Aspergillus colonization typically preceded the development of BOS by a median of 261 days (95% CI 87–520). Furthermore, in a multivariate Cox regression model, Aspergillus colonization was a distinct risk factor for BOS, independent of acute rejection. These data suggest a potential causative role for Aspergillus colonization in the development of BOS post-lung transplantation and raise the possibility that strategies aimed to prevent Aspergillus colonization may help delay or reduce the incidence of BOS.     

Living unrelated donors in kidney transplants: better long-term results than with non-HLA-identical living related donors?

BACKGROUND: Given the severe organ shortage and the documented superior results obtained with living (vs. cadaver) donor kidney transplants, we have adopted a very aggressive policy for the use of living donors. Currently, we make thorough attempts to locate a living related donor (LRD) or a living unrelated donor (LURD) before proceeding with a cadaver transplant. METHODS: We compared the results of our LURD versus LRD transplants to determine any significant difference in outcome. RESULTS: Between 1/1/84 and 6/30/98, we performed 711 adult kidney transplants with non-HLA-identical living donors. Of these, 595 procedures used LRDs and 116 used LURDs. Immunosuppression for both groups was cyclosporine-based, although LURD recipients received 5-7 days of induction therapy (antilymphocyte globulin or antithymocyte globulin), whereas LRD recipients did not. LURD recipients tended to be older, to have inferior HLA matching, and to have older donors than did the LRD recipients (all factors potentially associated with decreased graft survival). Short-term results, including initial graft function and incidence of acute rejection, were similar in the two groups. LURD recipients had a slightly higher incidence of cytomegalovirus disease (P=NS). We found no difference in patient and graft survival rates. However, the incidence of biopsy-proven chronic rejection was significantly lower among LURD recipients (16.7% for LRD recipients and 10.0% for LURD recipients at 5 years posttransplant; P=0.05). LRD recipients also had a greater incidence of late (>6 months posttransplant) acute rejection episodes than did the LURD recipients (8.6% vs. 2.6%, P=0.04). The exact reason for these findings is unknown. CONCLUSION: Although LURD recipients have poorer HLA matching and older donors, their patient and graft survival rates are equivalent to those of non-HLA-identical LRD recipients. The incidence of biopsy-proven chronic rejection is lower in LURD transplants. Given this finding and the superior results of living donor (vs. cadaver) transplants, a thorough search should be made for a living donor-LRD or LURD-before proceeding with a cadaver transplant.     

Acute native lung hyperinflation is not associated with poor outcomes after single lung transplant for emphysema.

BACKGROUND: Single-lung transplantation for emphysema may be complicated by acute native lung hyperinflation (ANLH) with hemodynamic and ventilatory compromise. Some groups advocate the routine use of independent lung ventilation, double-lung transplant, or right-lung transplant with or without contralateral lung volume reduction surgery in high-risk patients. The goal of this study was to determine the incidence of ANLH and identify its potential predictors. METHODS: We reviewed 51 consecutive single-lung transplants for emphysema. Symptomatic ANLH was defined as mediastinal shift and diaphragmatic flattening on chest x-ray with hemodynamic or respiratory failure requiring cardiopressor agents or independent lung ventilation. Preoperative and postoperative physiologic and hemodynamic data were analyzed from both recipients and donors. RESULTS: Sixteen patients developed radiographic ANLH; 8 were symptomatic, 2 severely so. We could not identify high-risk patients before transplant by pulmonary function tests, predicted donor total lung capacity (TLC)/actual recipient TLC ratio, pulmonary artery pressures, or the side transplanted. There was a trend toward an increased incidence of symptomatic ANLH in patients with bullous emphysema on chest computed tomography, but this was accounted for primarily by patients with alpha1-antitrypsin deficiency (4/13 vs 4/38 with chronic obstructive pulmonary disease, P = 0.10). No patient required cardiopulmonary bypass or inhaled nitric oxide intraoperatively. Patients with acute native lung hyperinflation did not have increased reperfusion edema as measured by chest x-ray score or PaO2/F(I)O2 ratio. Compared to patients without ANLH, symptomatic patients had longer ventilator times (64.9+/-14.6 hours vs 40.4+/-3.9, P = 0.02, ANOVA) and longer lengths of stay (19.3+/-2.1 days vs 13.7+/-1.3, P = 0.07), but 30-day survival was 100%. Two symptomatic patients required independent lung ventilation or inhaled nitric oxide; the others were managed with decreased minute ventilation, early extubation, and cardiopressor agents. No patient required early lung volume reduction surgery or retransplantation. Acute native lung hyperinflation had no effect on FEV1 or 6-minute walk results at 1 year; survival at 1, 2, or 3 years; or the rate of acute rejection, infection, or bronchiolitis obliterans syndrome greater than grade 2. CONCLUSION: Acute native lung hyperinflation is common radiographically but is rarely clinically severe. Although there was a trend toward an increase in symptomatic ANLH in patients with bullous emphysema, a high-risk group could not be identified preoperatively. Our results do not support the routine use of bilateral lung transplant, the exclusive use of right single-lung transplant, simultaneous lung volume reduction surgery, or independent lung ventilation for patients with emphysema. Management strategies should be employed that limit overdistension of the native lung and lead to early extubation.     

Outcomes of renal transplantation for recipients with lupus nephritis: analysis of the Organ Procurement and Transplantation Network database

Prior analyses of transplant outcomes in lupus transplant recipients have not consisted of multivariate analyses in the modern immunosuppressive era. Here, we compared patient and graft outcomes in lupus and non-lupus recipients transplanted between 1996 to 2000 using the United Network of Organ Sharing/Organ Procurement Transplant Network database. We evaluated the impact of recipient and donor demographic factors, time on dialysis and the initial immunosuppression regimen on rejection rates and transplant outcomes. Univariate analysis showed similar graft but better patient survival rates for primary lupus and non-lupus transplant recipients (5-year patient survival rates for lupus cohort 85.2% for deceased donor transplants and 92.1% for living donor transplants as opposed to 82.1% and 89.8% respectively for the non-lupus cohort; P=0.05 and 0.03) but similar patient survival rates for deceased donor retransplant patients. After controlling for confounding factors, no differences in patient or graft survival were seen between the two groups. No difference in acute rejection rates were observed in deceased donor transplants, but there was a small but significant increase in the risk of acute rejection in living donor lupus transplant recipients (hazard ratio=1.19, P=0.05). Risk of graft failure was lower for deceased donor recipients receiving MMF (five-year graft loss rate=29.6% for MMF vs. 40.2% for those not receiving MMF, P<0.0001), but no differences were seen among living donor recipients. Outcomes were similar regardless of type of calcineurin inhibitor, induction therapy, and time on dialysis. We conclude that lupus transplant recipients have outcomes generally equivalent to non-lupus transplant recipients.     

Immunologic and nonimmunologic factors: different risks for cadaver and living donor transplantation

BACKGROUND: There is a debate about the relative contribution of immunologic (rejection) and nonimmunologic (limited nephron mass) factors in long-term graft survival. METHODS: Using multivariate analysis, we studied the association of the following variables with outcome: delayed graft function (DGF), acute rejection, recipient race (black vs. nonblack), donor age (<50 vs. > or =50), donor race, and donor and recipient gender. Because of the association between DGF and rejection, recipients were grouped as follows: DGF, rejection; DGF, no rejection; no DGF, rejection; no DGF, no rejection. Data were analyzed on 1199 first kidney transplants in adults (752 living donor, 447 cadaver donor) done between January 1, 1985 and December 31, 1996. Two analyses were done: first, all transplants; second, only those with > or =1 year survival. For both, there was no difference in risk factors if death with function was or was not censored. RESULTS: For all cadaver transplant recipients, risk factors were acute rejection, DGF plus rejection, black recipient race, and donor age > or =50. For living donor recipients, only acute rejection was a risk factor. When only 1-year graft survivors were considered, risk factors were the same: for cadaver recipients, risk factors were acute rejection, DGF plus rejection, black recipient race, and donor age > or =50; for living donor recipients the risk factor was rejection. CONCLUSION: We found immunologic factors (rejection with or without DGF) to be significant in both living donor and cadaver donor transplants. Nonim. munologic factors (donor age, recipient race) were significant only in cadaver donor transplants.     

Lung transplantation for emphysema. Lung hyperinflation: incidence and outcome

Abstract Lung transplantation, single or bilateral sequential, is the final option for patients with emphysema. This study analyzed the outcome of lung transplants for emphysema (single or double), and evaluates the incidence, predictive factors and prognosis of lung hyperinflation (LHI) in unilateral transplants. We prospectively studied patients undergoing lung transplantation for emphysema. On admission to the Intensive Care Unit (ICU) and at 12, 24,48 and 72 h we tested the patients' respiratory function, oxygen arterial pressure (P_aO₂) and mean pulmonary arterial pressure (MPAP) before transplantation. LHI incidence, duration of mechanical ventilation and hypoxemia, ICU stay and mortality was also analyzed. We studied 34 consecutive patients undergoing lung transplantation for emphysema, 14 single and 20 bilateral. Single-lung transplantation had a higher mortality (50%) than double-lung transplantation (11%), with an odds ratio of 9.0 (1.3–48.7). Of the 14 patients who received a single graft, 9 patients (64%) developed LHI. No predictive factors for LHI could be established. Duration of mechanical ventilation (22 vs 3 days) and ICU stay (36 vs 6 days) was much longer in patients with LHI; however, only ICU stay reached statistical significance (P = 0.011). Mortality in patients with LHI was higher, 67% vs 20% (NS). We conclude that single-lung transplant in emphysema patients has a worse prognosis than bilateral transplant, with a 9-fold higher mortality rate. LHI is a common event in single-lung transplant for emphysema and is associated in our patients with a longer stay at the ICU.     

Living Donor Renal Transplantation Using Alemtuzumab Induction and Tacrolimus Monotherapy

Alemtuzumab was used as an induction agent in 205 renal transplant recipients undergoing 207 living donor renal transplants. All donor kidneys were recovered laparoscopically. Postoperatively, patients were treated with tacrolimus monotherapy, and immunosuppression was weaned when possible. Forty-seven recipients of living donor renal transplants prior to the induction era who received conventional triple drug immunosuppression without antibody induction served as historic controls. The mean follow-up was 493 days in the alemtuzumab group and 2101 days in the historic control group. Actuarial 1-year patient and graft survival were 98.6% and 98.1% in the alemtuzumab group, compared to 93.6% and 91.5% in the control group, respectively. The incidence of acute cellular rejection (ACR) at 1 year was 6.8% in the alemtuzumab group and 17.0% (p < 0.05) in the historic control group. Most (81.3%) episodes of ACR in the alemtuzumab group were Banff 1 (a or b) and were sensitive to steroid pulses for the treatment of rejection. There was no cytomegalovirus disease or infection. The incidence of delayed graft function was 0%, and the incidence of posttransplant insulin-dependent diabetes mellitus was 0.5%. This study represents the largest series to date of live donor renal transplant recipients undergoing alemtuzumab induction, and confirms the short-term safety and efficacy of this approach.     

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.     

Improving access to kidney transplantation without decreasing graft survival: long-term outcomes of blood group A2/A2B deceased donor kidneys in B recipients

BACKGROUND: The transplantation of blood group A2/A2B deceased donor kidneys into B recipients could improve access to transplantation for blood group B recipients. However, this practice is controversial, and long-term data are lacking. This study analyzed the long-term outcomes of A2/A2B deceased donor kidneys transplanted into selected B recipients. METHODS: We retrospectively assessed the outcomes (graft survival, transplant rates, and acute rejection) of deceased-donor kidneys using an allocation system that transplanted A2/A2B donors into B recipients with low anti-A blood group antibody titers between 1994 and 2003. Patients received conventional immunosuppression without any specific antibody reduction procedures. We further assessed the impact this system had on access to transplantation by blood group. RESULTS: Of 1,400 kidney transplants, 56 (4.0%) were A2/A2B to B recipients. The system reduced waiting time for all B recipients, even shorter than for blood group A recipients (median waiting times of A2/A2B to B transplants=182 days vs. B to B transplants=297 days; and A to A=307 days). Although there was a trend toward increased acute rejection in A2/A2B to B transplants, the actuarial 7-year death censored graft survival was 72% for B recipients regardless of donor type. CONCLUSIONS: Transplanting A2/A2B deceased donor kidneys into B recipients leads to an equalization of waiting time between blood groups with similar patient and graft survival using conventional immunosuppression. This protocol could lead to more equal access to kidney transplantation in blood group B recipients.     

Pulmonary transplantation.

OBJECTIVE: More than 2700 lung transplants have been performed since the initial clinical success in 1983. The evolution in the techniques of lung transplantation and patient management and the effects on results are reviewed. SUMMARY BACKGROUND DATA: Improvements in donor management, lung preservation, operative techniques, immunosuppression management, infection prophylaxis and treatment, rejection surveillance, and long-term follow-up have occurred in the decade following the first clinically successful lung transplant. A wider spectrum of diseases and patients treated with lung transplant have accentuated the shortage of suitable lung donors. The organ shortage has led to the use of marginal donors and a limited experience using living, related donors. METHODS: Changes in techniques and patient selection and management are reviewed and controversial issues and problems are highlighted. RESULTS: One-year survival of greater than 90% for single-lung transplant recipients and greater than 85% for bilateral lung transplant recipients have been achieved. Complications caused by airway complications has been reduced greatly. Obliterative bronchiolitis develops in 20% to 50% of long-term survivors and is the leading cause of morbidity and mortality after the first year after transplant. CONCLUSIONS: Lung transplantation has evolved into an effective therapy for a wide variety of causes of end-stage lung disease. Wider applicability requires solutions to the problems of donor shortage and development of obliterative bronchiolitis.     

Transforming growth factor-beta1 gene transfer ameliorates acute lung allograft rejection

BACKGROUND: The aim of the current work was to study the feasibility of functional gene transfer using the gene encoding for transforming growth factor-beta1, a known immunosuppressive cytokine, on rat lung allograft function in the setting of acute rejection. METHODS: The rat left lung transplant technique was used in all experiments, with Brown Norway donor rats and Fischer recipient rats. After harvest, left lungs were transfected ex vivo with either sense or antisense transforming growth factor-beta1 constructs complexed to cationic lipids, then implanted into recipients. On postoperative days 2, 5, and 7, animals were put to death, arterial oxygenation measured, and acute rejection graded histologically. RESULTS: On postoperative day 2, there were no differences in acute rejection or lung function between animals treated with transforming growth factor-beta1 and control animals. On postoperative day 5, oxygenation was significantly improved in grafts transfected with the transforming growth factor-beta1 sense construct compared with antisense controls (arterial oxygen tension = 411 +/- 198 vs 103 +/- 85 mm Hg, respectively; P =.002). Acute rejection scores from lung allografts were also significantly improved, corresponding to decreases in both vascular and airway rejection (vascular rejection scores: 2.0 +/- 0. 5 vs 2.8 +/- 0.6; P =.04; airway rejection scores: 1.3 +/- 0.7 vs 2. 3 +/- 0.8, respectively; P =.02). The amelioration of acute rejection was temporary and decreased by postoperative day 7. CONCLUSIONS: The feasibility of using gene transfer techniques to introduce novel functional genes in the setting of lung transplantation is demonstrated. In this model of rat lung allograft rejection, gene transfer of transforming growth factor-beta1 resulted in temporary but significant improvements in lung allograft function and acute rejection pathology.