Author + information
- Received April 11, 2013
- Revision received May 22, 2013
- Accepted June 17, 2013
- Published online December 17, 2013.
- Alanna A. Morris, MD∗∗ (, )
- Robert T. Cole, MD∗,
- Emir Veledar, PhD†,
- Naveen Bellam, MD, MPH∗,
- S. Raja Laskar, MD∗,
- Andrew L. Smith, MD∗,
- Howard M. Gebel, PhD∗,
- Robert A. Bray, PhD∗ and
- Javed Butler, MD, MPH∗
- ∗Emory University School of Medicine, Atlanta, Georgia
- †Emory University School of Public Health, Atlanta, Georgia
- ↵∗Reprint requests and correspondence:
Dr. Alanna A. Amyre Morris, Emory University School of Medicine, 1462 Clifton Road NE, Suite 520, Atlanta, Georgia 30322.
Objectives This study sought to investigate post-transplantation outcomes as a function of race and panel reactive antibody (PRA).
Background PRA screening is used to determine the presence of pre-formed antibodies to population-wide human leukocyte antigens (HLAs) in patients being evaluated for heart transplantation (HT). Racial/ethnic differences in long-term survival after HT have been described. However, whether there are significant racial/ethnic differences in PRA among adults awaiting HT is poorly characterized.
Methods We identified patients age ≥18 years in the Organ Procurement and Transplantation database with race/ethnicity of white, black, Hispanic, or Asian and listed for HT between 2000 and 2012 (N = 19,704). A PRA value of ≥10% was used to define clinically meaningful sensitization.
Results Blacks had a higher peak PRA than did all other groups and were more likely to be sensitized. Black HT recipients were more likely to experience graft failure than were Hispanic, white, and Asian recipients (31% vs. 27%, 26%, and 21%, respectively; p < 0.001). The median follow-up was 1,207 days (interquartile range: 373 to 2,364 days), with a trend toward a shorter median time to graft failure in the Asian group than in the black, Hispanic, and white groups (p = 0.065). Sensitized blacks had the lowest rate of allograft survival, whereas nonsensitized Asians had the highest survival. Using Cox proportional regression to adjust for other clinical variables, black race (HR: 1.3; 95% confidence interval [CI]: 1.2 to 1.5), Hispanic ethnicity (HR: 1.2; 95% CI: 1.0 to 1.5), and sensitization (HR: 1.2; 95% CI: 1.1 to 1.4) remained predictors of higher rates of graft failure.
Conclusions Race/ethnicity and level of sensitization are important predictors of graft survival.
Despite an overall trend toward improved outcomes after orthotopic heart transplantation (HT), disparities based on race and socioeconomic status (SES) persist. Racial/ethnic differences in long-term survival after HT are well recognized, with several studies demonstrating shorter graft and patient survival in HT recipients who are of racial/ethnic minority background (1–3). The exact mechanisms for these disparities are unclear; however, suggested explanations include SES factors and biological and immunologic mechanisms (1,4).
The impact of immunologic factors remains controversial; however, immunologic factors are likely to play an important role. For example, the impact of human leukocyte antigen (HLA) matching is disputed in cardiac allograft allocation; however, recipients of racial/ethnic minority background are more likely to have donor–recipient HLA mismatch (5) and are more likely to have an episode of rejection during the first year after transplantation (6). These differences may influence the observed racial disparities in post-transplantation outcomes, although this has not yet been convincingly demonstrated.
Panel reactive antibody (PRA) screening is used among patients being evaluated for HT to determine the presence of circulating antibodies to known HLA antigens in the general population, to assess the likelihood of finding a suitable donor, and to mitigate the risk for post-transplantation antibody-mediated rejection. The higher the PRA value, the greater the likelihood of a positive cross-match with a random donor, and the lower the likelihood of receiving a compatible transplant (7). Patients with higher PRA values tend to have extended waiting times while listed for solid-organ transplantation and lower rates of transplantation, although the use of solid-phase PRA assays has influenced these factors tremendously. At this time, the effect of race/ethnicity on clinically significant sensitization and its impact on post-transplantation outcomes remain unclear, so we sought to investigate wait-list characteristics and graft survival as functions of race/ethnicity and PRA.
All patients age ≥18 years of age who were listed for a primary HT in the United States between January 2000 and September 2012 were identified in the Organ Procurement and Transplantation Network (OPTN) database. The OPTN database includes data on all patients listed for a HT in the United States, as submitted by their transplantation centers. These data were provided to the investigators as de-identified data. The Health Resources and Services Administration and the U.S. Department of Health and Human Services provide oversight into the activities of the OPTN contractor, the United Network of Organ Sharing. Formal review was deemed unnecessary by the institutional review board at Emory University, Atlanta, Georgia.
Study design and definitions
We compared baseline characteristics and outcomes between white, black, Hispanic, and Asian patients listed for a primary HT during the study period. We excluded patients who were listed for a repeat HT or for multiorgan transplantation, and those who had missing values for PRA. The primary endpoint was graft failure in those patients who received a HT. Graft failure was chosen as the primary endpoint instead of patient survival because it allowed the inclusion of patients who had died, had received repeat transplantation, or did not have further information regarding their outcome of graft failure. Other clinical endpoints analyzed included time on the waiting list and risk for rejection in the first year after transplantation as functions of race, PRA, and HLA mismatch. Patients who received a HT were followed up until hospital discharge, death, or the day of last observation, with follow-up through September 2012.
Demographic and clinical variables were defined at the time of listing (for wait-list outcomes) and at the time of transplantation (for post-transplantation outcomes). Race was reported by the transplantation centers as one of the following: white, black, Hispanic/Latino, Asian, American Indian/Alaska Native, Native Hawaiian/Pacific Islander, multiracial, and other. Ethnicity was reported as Hispanic or non-Hispanic. For all Hispanic patients in the study, race and ethnicity variables were identical; therefore, all white patients in this analysis were non-Hispanic white, and all black patients were non-Hispanic black. Because of the small sample size of minority patients with race/ethnicity other than black, Hispanic, or Asian (<1% of the sample), these patients were excluded from this analysis.
PRA was analyzed as: 1) a continuous variable based on both the most recent value and the peak value; and 2) a categorical variable in which most recent PRA or peak PRA of ≥10% was considered sensitized. HLA matching was analyzed as: 1) a continuous variable on the basis of the number of mismatches; and 2) as a categorical variable based on a value greater than or equal to the median number of mismatches.
Clinical variables assessed for which none of the patients had missing data included: age, sex, blood type, body mass index (BMI), history of diabetes, renal function, wait-list status (transplantation, death, or removal from the wait-list), hemodynamic support (intra-aortic balloon pump, temporary or durable mechanical support), mean pulmonary artery pressure and pulmonary capillary wedge pressure, type of medical insurance, level of education, and donor age. Other clinical variables assessed included number of prior pregnancies, prior blood transfusion (dichotomized), and allograft ischemic time.
Data are presented as median (interquartile range [IQR]) or as n (%) of patients. Baseline characteristics were compared between racial/ethnic groups using the chi-square test for categorical variables and the Kruskal-Wallis test for continuous variables. Univariate and multivariate Cox proportional hazards models were developed using a forward-selection procedure, retaining variables significant at the 0.20 level, on the basis of a likelihood ratio test; all variables in Table 1 were considered. Finally, we assessed the association of race/ethnicity with the primary endpoint to evaluate the consistency of this relationship and to assess the interaction of race/ethnicity with other variables.
Data were analyzed with the use of SAS version 9.3 (SAS Institute Inc., Cary, North Carolina).
During the study period, 33,037 U.S. patients ≥18 years of age were listed for a primary HT. Of these, 13,126 patients had missing PRA values and so were excluded from the analysis. An additional 207 patients were excluded for race/ethnicity other than white, black, Hispanic, or Asian. The remaining 19,704 patients formed the analytic cohort for this study.
Table 1 summarizes the baseline characteristics of the study population. Black recipients were younger and had a higher proportion of female recipients than did the other 3 racial/ethnic groups. Hispanic recipients were more likely to have O blood type. Hispanic and Asian recipients were more likely to have a history of diabetes and less likely to have received a ventricular assist device (VAD). Black and Hispanic recipients were more likely to have had Medicaid or Medicare as their primary payer and had a lower mean level of education. Black and Hispanic recipients were more likely to have had multiple pregnancies but were less likely to have had prior blood transfusions. Allograft ischemic time was shorter in black and Hispanic recipients, and donor age was younger in Hispanic and Asian recipients.
PRA and HLA mismatch
Table 2 summarizes the median values for the most recent and peak PRA, and the frequency of HLA mismatch by race/ethnicity. Black recipients had higher peak PRA than did the other 3 groups, and had higher most recent PRA values than did the white and Hispanic recipients. Compared with whites, all race/ethnic minorities had a higher level of HLA mismatch.
Influence of PRA on wait-list times
Overall, the median time on the wait-list was longest in whites and shortest in Asians (Table 1). Sensitized recipients had longer median wait times than did nonsensitized recipients (111 [IQR: 37 to 277] days vs. 66 [IQR: 21 to 186] days; p < 0.001). Figure 1 illustrates the cumulative proportion of patients who underwent HT by 180 days according to sensitization (Fig. 1A) and according to race and sensitization (Fig. 1B). After adjusting for BMI, blood type, sensitization, presence of VAD at transplantation, and region, both black and Hispanic race/ethnicity (beta: 0.046; p < 0.001) and peak PRA (beta: 0.146; p < 0.001) were independently associated with longer wait times.
Influence of PRA and HLA mismatch on treatment for rejection post-transplantation
Overall, the likelihood of being treated for rejection within 1 year of HT was 20.8% among all HT recipients and was similar between sensitized and nonsensitized patients (20.4% vs. 20.9%; p = 0.4). In nonsensitized patients, black recipients were the group most likely to be treated for rejection within 1 year of HT (564 [31%] vs. 2,405 [27%], 237 [27%], and 59 [22%] in whites, Hispanics, and Asians, respectively; p = 0.005). In sensitized patients, however, there was no statistical difference in the likelihood of being treated for rejection based on race/ethnicity (202 [31%] vs. 562 [28%], 47 [25%], and 19 [25%]; p = 0.2).
The likelihood of being treated for rejection within 1 year of HT was higher in HT recipients with HLA mismatch at ≥5 loci compared with those with less HLA mismatch (63% vs. 58%; p < 0.001). In recipients with HLA mismatch at ≥5 loci, Asian recipients were the least likely to be treated for rejection within 1 year of HT (40 [20%] vs. 1,562 [29%], 183 [31%], and 491 [32%] in whites, Hispanics, and blacks, respectively; p = 0.001). In recipients with HLA mismatch at <5 loci, however, there was no statistical difference in the likelihood of being treated for rejection between racial/ethnic groups.
Post-transplantation graft failure
Thirty-three patients (0.2%) died during the transplantation procedure. The median follow-up time in the recipients who survived transplantation was 1,207 days (IQR: 373 to 2,364 days), with 580 recipients (3%) deemed lost to follow-up. Overall, 5,314 recipients (26%) were reported to have experienced graft failure during the study period. Of these, 5,098 recipients (96%) died and 200 (3.7%) underwent repeat transplantation; 16 recipients (0.3%) did not have further information regarding the outcome of graft failure. The most commonly reported causes of death included cardiovascular (16%), infection (15%), multiorgan failure (9%), malignancy (8%), and rejection (8%). The most commonly reported causes of graft failure were rejection (52%) and primary graft failure (35%). Univariate predictors of graft failure included age, female sex, black and Hispanic race/ethnicity, education, insurance type, prior transfusion, prior pregnancies, presence of VAD, renal dysfunction, BMI, sensitization, HLA mismatch, donor age, and allograft ischemic time (Table 3).
Overall rates of graft survival at 1 and 5 years in whites, blacks, Hispanics, and Asians were 85% and 72%, 79% and 63%, 84% and 67%, and 85% and 75%, respectively. Black HT recipients were more likely to experience graft failure than were Hispanic, white, and Asian recipients (31% vs. 27%, 26%, and 21%; p < 0.001). There was a trend toward a shorter median time to graft failure in Asians than in blacks, Hispanics, and whites (411 [IQR: 46 to 1,081] days vs. 509 [IQR: 113 to 1,371], 584 [IQR: 83 to 1,530], and 576 [IQR: 64 to 1,760] days; p = 0.065).
Figure 2 illustrates the probability of graft survival on the basis of race/ethnicity and presence of sensitization. Sensitized blacks had the lowest graft survival, whereas nonsensitized Asians had the highest graft survival. In multivariate analysis adjusted for age, sex, BMI, insurance status, level of education, prior transfusion, prior pregnancies, HLA mismatch, renal function, presence of VAD, and donor age and allograft ischemic time, black race (adjusted HR: 1.3; 95% CI: 1.2 to 1.5), Hispanic ethnicity (adjusted HR: 1.2; 95% CI: 1.0 to 1.4), and sensitization (adjusted HR: 1.2; 95% CI: 1.1 to 1.4) remained significant predictors of higher probability of graft failure (Table 4). Formal testing for interaction of race with sensitization was not significant (p = 0.5). Other multivariate predictors of graft failure included having Medicaid/Medicare insurance, renal dysfunction, HLA mismatch, older donor age, and longer ischemic time.
In this study, we report that: 1) black and Hispanic patients continue to have higher rates of graft failure than did other racial/ethnic groups, and the risk for graft failure was highest in blacks with high PRA levels; 2) HLA mismatch was related to graft failure in our sample, and racial/ethnic minorities were more likely to have HLA mismatch compared with white HT recipients; and 3) there appeared to have been a trend toward decreased risk of rejection requiring treatment and graft failure in Asian HT recipients despite higher PRA levels and more HLA mismatch compared with their white counterparts.
Our findings support and extend previous data showing higher mortality in black and Hispanic HT recipients. Prior large analyses from the OPTN database have consistently shown worse outcomes in blacks, including higher risks for rejection, hospitalization, and death, even after adjustment for the higher clinical risk profile often seen pre-transplantation in black patients (1,4,8). Other investigators have reported higher PRA levels in black patients (9,10); however, there are little data to date reported on PRA levels in HT recipients of Hispanic ethnicity. Although the black patients in our cohort had higher PRA levels, the differences in the degree of sensitization did not fully account for the differences in outcomes; black race remained a significant predictor of graft failure after adjustment for recipient, transplant, and SES factors.
Immunologic mechanisms have been implicated as a cause of the higher rates of graft failure seen in minority transplant recipients. Prior studies have suggested heightened immunologic responsiveness, as well as differences in immunosuppressant drug metabolism (11) and responsiveness (12), as contributors to differential responses to allograft transplantation in minority racial/ethnic groups. Additionally, genetic variations put blacks and Hispanics at increased risk for receipt of grafts poorly matched for HLA antigens compared with white transplant recipients (5,13,14). Unfortunately, the complexity of the genetic composition of HLA antigens and the relative paucity of organ donors of minority background make it exceptionally difficult to achieve equitable matching in racial/ethnic minorities compared with whites in the United States, particularly among blacks. Furthermore, the use of HLA matching for solid-organ transplantation remains highly controversial in part because the risk for mismatch is high in all groups irrespective of race due to the extensive polymorphism of the HLA system, and the average number of antigens mismatched does not vary greatly among different racial/ethnic groups (14). There are conflicting data regarding HLA matching on allograft survival, as some studies have suggested that HLA mismatch number did not affect time to first rejection or rejection frequency among black patients (15,16), whereas others have found HLA mismatch related to worse outcomes (5). Our data suggest that HLA mismatch did indeed increase the likelihood of graft failure over the study period. More investigation is needed to clarify the effects of HLA matching in HT.
Interestingly, the higher levels of PRA and HLA mismatch seen in Asian HT recipients in our cohort did not appear to affect a higher risk for graft failure. Prior data have shown lower rates of sensitization in Asians compared with other racial/ethnic groups (17). In our cohort, Asians were the second-most sensitized group, likely due to a fairly high prevalence of prior blood transfusions. Other studies have also shown HT recipients of Asian race to have significantly reduced rates of rejection compared with other racial/ethnic groups (3,18). Data from kidney transplant recipients have also shown superior graft survival in Asian recipients, and the authors speculate that the reason for this could be more favorable pre-transplantation characteristics, such as a lower BMI; fewer comorbidities; and higher levels of education, which might give rise to better compliance and, hence, better outcomes post-transplantation (19). A prior report from a single-center experience has also shown superior graft survival in Asian HT recipients (3). To the best of our knowledge, ours is the largest series in HT recipients in the United States confirming the lower risk for rejection and superior graft survival in Asians, despite higher degrees of sensitization and HLA mismatch. The mechanisms for this protective effect are unclear; however, the findings warrant further investigation.
Other mechanisms certainly contribute to worse outcomes in racial/ethnic minorities, including SES. Black and Hispanic HT recipients have been shown in prior studies to be less educated and more likely to have Medicaid as their primary payer (4,6), and these differences were supported in this cohort. However, adjusting for education and insurance status did not appear to eliminate the differences in graft survival in our analysis. A prior report in 525 HT recipients showed that low SES and nonwhite ethnicity were both associated with risk for graft loss and risk for rejection episodes (4). Similar to our findings, that study showed that low SES modestly lowered the impact of nonwhite race on graft loss, but that both SES and race appeared to be of independent predictive value. Those authors speculated that SES factors might amplify the effects of biological differences in racial groups on outcomes. Certainly there could be other SES factors or confounders that are unaccounted for in our model; however, our data strongly suggest that the observed differences are not explained by SES alone.
Prior data suggest that comprehensive care may abrogate many of the racial/ethnic disparities observed in other cohorts. Despite worse pre-transplantation hemodynamic profile, higher pre-transplantation PRA levels, and more post-transplantation hospitalizations and episodes of rejection in black patients, Pamboukian et al. (20) reported no difference in 5-year survival in their series. In this series, black patients had more intense utilization of both outpatient and inpatient resources. These authors concluded that aggressive surveillance and medical intervention may negate some of the effects of a greater risk for rejection in black patients.
There have been significant advances in both HLA and PRA technology during the current era (21,22) that may have affected the reported results. For instance, most centers have evolved from the use of complement-dependent cytotoxicity testing to PRA assays based on flow cytometry. However, we cannot fully account for how the use of different assays may have affected our findings. Furthermore, even with current methods, the degree of sensitization represented by PRA can be highly variable and inconsistent because the value of PRA depends both on the panel composition and the technique used for antibody detection. Because the percent reactivity of the panel depends on the composition of the donor pool, it is possible that donor pools are more likely to have a substantial number of white donors, leading to higher panel reactivity in racial/ethnic minorities. We also did not have information on calculated PRA, which corresponds to the frequency of unacceptable antigens in a large population of HLA-typed United Network of Organ Sharing donors, and more accurately assesses the likelihood of a sensitized patient to be compatible with a deceased donor (22). Next, we did not adjust for center volume, which may affect post-transplantation outcomes. Prior studies have shown that black and Hispanic patients are more likely to be listed at low-volume centers; however, adjusted analyses have shown that center volume does not account for racial/ethnic differences in post-transplantation mortality (6). Finally, race/ethnicity is by self-report, and in particular it is unclear whether patients who were identified as Asian were of South or East Asian descent, as the cardiovascular profiles often differ in these groups.
Black and Hispanic patients are at a higher risk for graft failure post-transplantation, with sensitized blacks having the poorest long-term outcomes. Despite substantial improvements during the current era in the application of HLA technology, clear disparities exist that put certain racial/ethnic minorities at higher risk for allograft failure independent of differences in SES. These gaps in post-transplantation outcomes warrant further investigation.
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- body mass index
- human leukocyte antigen
- heart transplant
- panel reactive antibody
- socioeconomic status
- ventricular assist device
- Received April 11, 2013.
- Revision received May 22, 2013.
- Accepted June 17, 2013.
- American College of Cardiology Foundation
- Singh T.P.,
- Almond C.,
- Givertz M.M.,
- Piercey G.,
- Gauvreau K.
- Singh T.P.,
- Almond C.S.,
- Taylor D.O.,
- Milliren C.E.,
- Graham D.A.
- Liu V.,
- Bhattacharya J.,
- Weill D.,
- Hlatky M.A.
- Schaffer J.M.,
- Singh S.K.,
- Reitz B.A.,
- Oyer P.E.,
- Robbins R.C.,
- Mallidi H.R.
- Jarcho J.,
- Naftel D.C.,
- Shroyer T.W.,
- et al.,
- the Cardiac Transplant Research Database Group
- Katznelson S.,
- Bhaduri S.,
- Cecka J.M.
- Kilic A.,
- Weiss E.S.,
- Allen J.G.,
- et al.
- Goh A.