Ann Thorac Surg 2008;85:1919-1924. doi:10.1016/j.athoracsur.2008.02.011
© 2008 The Society of Thoracic Surgeons
Original Articles: General Thoracic
Pretransplant Panel Reactive Antibodies in Human Lung Transplantation: An Analysis of Over 10,000 Patients
Ashish S. Shah, MD*,
Lois Nwakanma, MD,
Christopher Simpkins, MD,
Jason Williams, MD,
David C. Chang, PhD,
John V. Conte, MD
Division of Cardiac Surgery, Department of Surgery, Johns Hopkins Medical Institute, Baltimore, Maryland
Accepted for publication February 4, 2008.
* Address correspondence to Dr Shah, Division of Cardiac Surgery, The Johns Hopkins Hospital, Blalock 618, 600 N Wolfe St, Baltimore, MD 21287 (Email: ashah29{at}jhmi.edu).
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Abstract
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Background: The role of panel reactive antibody (PRA) in lung transplant recipients has not been clearly defined in a large population. We sought to determine how panel reactive antibody level affects survival in lung transplant recipients.
Methods: The United Network for Organ Sharing (UNOS) Standard Transplant Analysis and Research files from 1987 through 2005 were analyzed. Demographic data, pretransplant PRA, relevant clinical indicators, and survival were examined.
Results: Of the 12,751 first lung transplant recipients during this period, pretransplant PRA levels were reported for 10,237 patients. Panel reactive antibody was more than 0% in 1748 patients; of these, PRA was 1% to 10% in 1259 (72%), 11% to 25% in 249 (14%), and more than 25% in 240 (14%). Using the Kaplan-Meier method, survival decreased with increasing PRA and was significant when PRA exceeded 25% compared with the rest of the cohort. On multivariable analysis, PRA was associated with increased 30-day (hazard ratio, 2.6) and overall mortality (hazard ratio, 1.3). Importantly, this effect was not seen when a cohort from 1998 through 2005 was analyzed.
Conclusions: The UNOS database has provided the largest series of lung transplant patients stratified by PRA. Our analysis demonstrates that PRA level exceeding 25% is a predictor of death. However, newer laboratory and management techniques may attenuate this effect with better outcomes in the modern era.
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Introduction
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The effect and influence of preformed antihuman leukocyte antigen (HLA) antibodies or panel reactive antibodies (PRA) in human lung transplantation remains unclear. Relevant studies are limited owing to the small numbers of patients, evolving clinical management, and conflicting results. Further work has also implicated these antibodies in the development of bronchiolitis obliterans syndrome (BOS) and acute cellular rejection [1–10].
The United Network for Organ Sharing (UNOS) maintains a database of transplant outcomes in the United States and captures preoperative PRA status. In the present report, we examined the effect of sensitization on survival after human lung transplantation.
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Patients and Methods
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Patient Population
Data reported to the UNOS registry for lung transplantation performed between October 1, 1987, and September 31, 2005, were analyzed. This time period was further divided into two eras: 1987 through 1997 and 1998 through 2005. We identified 10,237 first lung transplant recipients and 1748 within this cohort who had a PRA exceeding 0% (PRA-positive). Of the PRA-positive patients, 1259 (72%) had a PRA from 1% to 10%, 249 (14%) from 11% to 24%, and 240 (14%) exceeded 25%. In dividing the overall cohort by eras, 5070 were in the earlier era (1987 through 1997) and 6908 in the modern era (1998 through 2005).
Statistical Analyses and Survival
Data from the UNOS Standard Transplant Analysis and Research files were imported into Stata 9.0 software (StataCorp, College Station, TX), which was used for statistical computations. For all statistical tests values of p < 0.05 were considered significant. All means are reported as mean ± standard deviation. Univariate comparison of continuous variables was performed using a Student t test or Wilcoxon–Mann-Whitney test. Associations between categoric variables were tested by using the Pearson 
2 test. Actuarial survival was compared using the Kaplan-Meier method, and statistical differences between survival curves were assessed by the log-rank test. Multivariate analyses were performed by Cox proportional hazards regression to determine independent predictors of death.
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Results
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Demographics
Panel reactive antibody effect on death was analyzed in a variety of subgroups. Table 1
summarizes basic demographics in the cohort. Patients were also stratified into four PRA levels. Of note, a higher percentage of women had an increasing PRA. The distribution of single- and double-lung transplants was similar in all subgroups. The remaining demographic variables were evenly distributed among subgroups. Patients were also divided into high and low PRA groups. Patients with a PRA of less than 25% were compared with those with a PRA exceeding 25%. Here, women comprised a higher proportion those with a PRA exceeding 25%, and the diagnosis of cystic fibrosis was more common in the lower PRA group (Table 2).
To examine the effect of transplant era, patients were divided into two time periods. Patients who received a transplant from 1987 through 1997 were compared with patients who underwent transplantation from 1998 through 2005. The patients in the more modern group were older and fewer had primary pulmonary hypertension (Table 3).
Analysis of the Entire Cohort
Analysis of Kaplan-Meier survival among the four PRA subgroups shows a statistically significant difference in outcome (Fig 1). Patients with a PRA exceeding 25% had survival of 69% at 1 year and 40.1% at 5 years, which is significantly less compared with those with a PRA of 0%. Patients with lower levels of PRA did not have significantly different survival. In dividing the group by high and low PRA, this survival disadvantage is again seen in Figure 2.
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Fig 1. Kaplan-Meier estimates of mortality, 1987 through 2005, stratified by four groups of panel reactive antibody (PRA) levels (0%, blue; 1 to 10, red, 11 to 25, green; and > 25, orange). Actuarial survival was calculated for the entire cohort and stratified by PRA level. *Comparison between each group and reference point PRA = 0% by log-rank test.
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Fig 2. Kaplan-Meier estimates of mortality, 1987 through 2005, stratified by panel reactive antibody (PRA) level of 25% or less (blue line) or exceeding 25% (orange line). Actuarial survival compares patients with a PRA exceeding 25% vs those with less than 25%.
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Effect of Procedure Type in Panel Reactive Antibody Exceeding 25%
In patients with a high PRA (PRA > 25%), there was no survival advantage of single vs bilateral lung transplantation (Fig 3). One-year survival was 66.9% for single-lung transplants and 70% for bilateral-lung transplants.
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Fig 3. Kaplan-Meier estimates of mortality, 1987 through 2005 for panel reactive antibody (PRA) exceeding 25%, stratified by type of transplant (TX). Actuarial survival in highly sensitized patients is divided by procedure type. There was no significant difference between single- (SLT, green line) and bilateral-lung transplant (BLT, orange line) recipients.
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Multivariable Analysis
Multivariable analysis was performed on the entire cohort to examine the interaction of risk factors for long-term survival. Panel reactive antibody expressed as both a continuous and dichotomous variable was associated with death in a multivariable model. Donor age, cigarette use exceeding 20 pack/years, recipient steroid use, and single-lung transplant were also associated with long-term mortality (Table 4).
To examine effect of PRA on early death, the multivariable analysis was performed using 30-day mortality as the end point. In this model, PRA was strongly associated with early death (hazard ratio, 2.67). Body mass index and year of transplant were also associated with 30-day mortality (Table 5).
Effect of Transplant Era
Because continuous improvements have occurred in the care of sensitized lung transplant patients, the cohort was divided into two eras: 1987 through 1997 and 1998 through 2005. In the older cohort, patients with a PRA exceeding 25% had significantly worse survival. Kaplan-Meier analysis of the more modern cohort showed no survival difference when patients with PRA exceeding 25% were compared with those with a PRA of less than 25%. Survival at 1 and 5 years was 80.1% and 49% in the low PRA group and 75% and 48% in the high PRA group (Fig 4A and B).
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Fig 4. (A) Kaplan-Meier estimates of actuarial survival, 1987 through 1997, stratified by panel reactive antibody (PRA) level of 25% or less (blue line) vs exceeding 25% (orange line). Patients with a PRA exceeding 25% have significantly decreased survival compared with patients with a PRA of less than 25%. (B) Kaplan-Meier estimates of actuarial survival in a more modern cohort, 1998 through 2005, stratified by PRA level of less than 25% (blue line) vs exceeding 25% (orange line). Patients with a PRA exceeding 25% did not have a statistically significant survival difference compared with patients with a PRA of less than 25%.
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Comment
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We used the large UNOS data set for lung transplant performed between 1987 and 2005 to examine the effect of sensitization. Elevated PRA exceeding 25% was associated with early death in the entire cohort; however, this effect was no longer seen in a more modern era.
The role of preformed antibodies has been the center of extensive study in renal transplantation [11, 12]. Because of the rarity of sensitized lung transplant patients, only small sample sizes have been reported. Gammie and colleagues [13] reported a single-center experience that showed no difference in survival among 20 patients with a PRA exceeding 10%. Lau and colleagues [14] were unable to show a survival disadvantage for their 18 PRA-positive patients. Finally, Hadjialis and colleagues [6] combined the Toronto and Duke experience to generate a larger cohort; here, a PRA exceeding 25% was associated with worse long-term survival. Only 20 patients in that study had a PRA exceeding 25% [6].
Nonetheless, PRA-positive patients have higher reported rates of cellular rejection and BOS rates. Grinita and colleagues [10] showed that both preoperative PRA-positive patients and those in whom antibodies develop after transplantation have higher rates of cellular rejection and BOS.
The current study reports a large series of PRA-positive patients across nearly 20 years of clinical lung transplantation in the United States. The evaluation of the entire group showed a persistent survival disadvantage to a PRA exceeding 25%. This effect was early, because high PRA was strongly associated with 30-day mortality.
This phenomenon, however, did not reach statistical significance in the recent era (1998 through 2005). Kaplan-Meier survival was not different in the high PRA (>25%) group compared with the rest of the cohort for that era. There are number of explanations for this finding. After 1996, widespread use of enzyme-linked immunosorbent assay testing for preformed antibodies improved the sensitivity of testing. Further advances in testing involve flow cytometric methods and the use of single-antigen testing [15, 16]. All of this allows for specific and dependable testing of patients both before and after operation.
The ability to avoid specific antigens in donors, allowing for "virtual" crossmatching, has significantly reduced the need for formal preoperative crossmatching in our practice and potentially eliminates the immunologic morbidity of preformed donor-specific antibody [17]. Thus, being PRA-positive today may not have the same meaning as it did in the previous era.
More sensitive testing should result in a truly high-risk group of patients. Yet outcomes are better. This suggests that treatment for the sensitized patients has also improved [18]. In addition to prospective crossmatching, many centers are using set protocols that include immunoglobulin, plasmapheresis, and rituximab. Using a protocol of plasmapheresis, weekly immunoglobulin, and twice weekly antibody testing, we have had no early deaths or hyperacute rejection in 4 highly sensitized patients despite positive retrospective cytotoxic crossmatches in 3 patients. Finally, the increased use of mycophenolate mofetil may have affected outcomes. Mycophenolate mofetil has activity against B-cells and as a result may blunt B-cell activation in these immunologically primed patients [19].
The evaluation of preformed antibodies is undergoing significant change. As was discussed, HLA antibodies detection began with complement-dependant techniques, then solid-phase assays, and now includes very sensitive flow cytometric methods and single antigen beads. Testing has also moved from donor-specific qualitative tissue assays to the ability to report the particular strength or titer of the antibody [20]. How this information should be used is unclear because data that examine preoperative antibody strength and outcome in lung transplantation are lacking. Certainly, the presence of donor-specific antibodies merits treatment, and modern treatment protocols may account for the improved outcomes. What is even less clear, however, is the risk of third-party and low-titer donor-specific antibodies.
Does the presence of preformed anti-HLA antibodies matter in lung transplantation? In the UNOS data set, a PRA exceeding 25% is associated with increased death. However, our study would also suggest that from 1998 through 2005, highly sensitized patients no longer have the same mortality risk. The risk of rejection and chronic allograft failure was not evaluated and likely remains an important problem.
A limitation of the study is that it is based on a registry. The clinical management of sensitized patients varies. Testing is not standardized, and reporting in the database may be inconsistent. Fortunately, death in the UNOS data set is verified in multiple ways. We chose not to examine issues related to specific antibody class, rejection, and graft function owing to the incomplete data set. Statistical methods may be used to account for incomplete records, but our interest was in the outcome death.
In conclusion, the current study used the UNOS database to examine the problem of preoperative sensitization in adult lung transplantation. We found that looking over a period from 1988 through 2005, a PRA level exceeding 25% was a strong predictor of early death. This effect was not seen in a modern era. Our study highlights unique immunologic behavior in pulmonary transplantation. Future studies will examine the issues of antibody strength, de novo development of antibodies, and better immunologic characterization on patient and graft outcome.
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References
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- Hammond EH, Howell RL, Nunda S, et al. Vascular (humoral) rejection in heart transplantation; pathologic observations and clinical implications J Heart Transplant 1989;8:430-443.[Medline]
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- Leffell MS, Montgomery RA, Zachary AA. The changing role of antibody testing in transplantation Clin Transpl 2005:259-271.
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Abstract
Introduction
