Increased cPRA is associated with increased waitlist time and mortality in LTx

Abstract

Purpose

Sensitized candidates with unacceptable antigens are a group that demands special attention in solid organ transplantation. Calculated panel reactive antigen (cPRA) is not used to modify allocation priorities in lung transplantation. The impact of cPRA on waiting list time and mortality is unknown.

Methods

We performed a retrospective cohort review of candidates for lung transplantation listed from May, 2005 to 2018. Data from OPTN/UNOS Standard Analysis and Research (STAR) dataset was paired with additional unacceptable antigen (UA-HLA) data, which was used to calculate the listing cPRA. Candidates were stratified based upon lack of UA-HLA or cPRA level for candidates with unacceptable antigens reported. Unadjusted competing risks and adjusted sub-distribution hazard models were fit.

Results

A total of 29,085 candidates met inclusion criteria for analysis. Of these N = 23,562 (81 %) with no UA-HLA, N=3,472 (11.9%) with cPRA < 50, and N=2,051 with cPRA ≥ 50 (7.1%). On adjusted analysis, cPRA ≥ 50 was independently associated with increased waitlist mortality at 1-year (HR 1.71, 95% CI 1.55–1.88, p < 0.001) and decreased rate of transplantation (71.9% Vs 69.5% Vs 44.4%; respectively, P < 0.001). Furthermore, patients with cPRA ≥ 50 had a longer waitlist time compared with cPRA < 50 and no UA-HLA candidates (mean 293.69 days vs 162.38 and 143.26 days, respectively, p < 0.001). Once transplanted, however, post-transplant survival among the cohorts was similar.

Conclusions

Further evaluation of organ allocation with consideration of candidate cPRA may be warranted in order to optimize equity in access to transplants (Graphical abstract).

Graphical Abstract

Introduction

Lung transplantation offers both survival and quality of life improvements to patients with end-stage lung disease who otherwise have few treatment options available. Although a consistent rise in the number of transplants performed each year, an ongoing mismatch exists between donor organ supply and the demand for suitable organs (1–3). As such, candidates with end-stage lung disease continue to spend a significant amount of time awaiting a suitable allograft, exposing candidates to the risk of waitlist mortality. Candidates with allosensitization with human leukocyte antigen (HLA) antigens are at risk for further delays due to a desire to exclude donors with incompatible HLA antigens that might lead to hyperacute rejection.

In contemporary solid-organ transplantation, a candidate’s degree of sensitization is quantified by the calculated panel-reactive antibody (cPRA), a comparison of a candidate’s unacceptable antigens and the frequency of those HLA antigens in the donor population. While center-specific differences exist in the techniques and thresholds employed to ascertain UA-HLA differ, cPRA represents the nationally-employed measure to report sensitization in candidates for transplantation. The development and implementation of the virtual crossmatch, in which a donor without specific unacceptable HLA antigens can be identified for a candidate (through solid-phase techniques for the assessment of HLA antibody specificity) permits broader access to donors for candidates with a high degree of sensitization. Despite improved ability to identify suitable allografts, sensitized recipients continue to suffer worse waitlist and posttransplant survival in single-center reports (4,5). While these findings mirror those in nationally-representative analyses of heart transplantation, they have yet to be examined in a nationally-representative cohort in lung transplantation (6–8).

Under the current allocation system, a high degree of sensitization is not factored in to waitlist priority for lung transplant candidates. On account of data to suggest negative waitlist outcomes for renal transplant candidates, adjustments were made to renal allograft allocation to prioritize the allocation of compatible allografts to highly-sensitized candidates and improve waitlist outcomes. To determine the degree to which UA-HLA (and cPRA) contribute to negative outcomes for candidates awaiting lung transplantation, and to determine if consideration of sensitization of lung transplant candidates may make allocation more equitable, we performed a retrospective cohort study using a nationally representative transplantation database.

Methods

Data Source

We performed a retrospective cohort analysis using data from the United Network of Organ Sharing (OPTN/UNOS) Standard Analysis and Research (STAR) dataset. UNOS administers the Organ Procurement and Transplantation Network (OPTN) under contract with the U.S. Department of Health and Human Services (HHS). This database contains data on all transplant candidates undergoing listing for solid organ transplantation in the United States since October 1987. The dataset used for this investigation included all candidates listed for lung transplantation between May 2005 (time of introduction of the Lung Allocation Score) and January, 2018. Unacceptable antigen (UA) data were provided by UNOS, which was used to calculate the pre-transplant cPRA (for candidates that provided UA data). UNOS HLA equivalency tables and antigen frequencies were employed to facilitate calculation of cPRA from UA-HLA entered for each candidate that reported unacceptable antigens as described by Kransdorf, et al (8). Candidates that reported no UA-HLA data were treated as a distinct control group for comparison to candidates that reported UA-HLA and therefore had a calculable cPRA. As of 1999, all data in the OPTN/UNOS transplantation database has been collected via an internet-based database application called “UNet.” Data were entered by transplant professionals. Electronic data validation and on-site audits are performed for quality assurance. The institutional review board (IRB) at Duke University approved this study prior to data collection.

Study Design

All first-time adult candidates listed for isolated lung transplantation during the study dates were included for analysis. Exclusion criteria included candidates < 12 years old, those listed for simultaneous heart, liver, or abdominal transplantation, and those with incomplete survival or Lung Allocation Score (LAS) data. Candidates were stratified based upon lack of unacceptable antigen data (no UA-HLA data reported) or cPRA for candidates with unacceptable antigens reported (Figure 1).

Figure 1:

Study cohort diagram showing inclusion and exclusion criteria.

Statistical Analysis

Demographic data were compiled and described. Baseline characteristics and outcomes were compared between groups using the Kruskal-Wallis analysis of variance test for continuous variables and Pearson’s Chi-squared test for categorical variables.

cPRA was examined both as a continuous and categorical variable to permit comparison to the control group without any UA-HLA data reported. Restricted cubic splines were used to explore potential nonlinear relationships between continuous cPRA and waitlist mortality in a univariate cox proportional hazards model. Relationships were plotted as curves for cPRA versus log hazard of waitlist mortality. As a sensitivity analysis, this relationship was again examined in an adjusted fashion, in which age, gender, initial LAS, need for ventilator at listing, and need for ECMO at listing were incorporated into the cox proportional hazards model for waitlist mortality. Inspection of the relationship between continuous cPRA and waitlist mortality was used to inform categorization of cPRA to permit competing-risks analysis and comparison to the control group described above without UA-HLA data submitted. Candidates were censored at the time of transplantation or recovery for this model.

Cumulative incidence functions were employed to examine the cumulative incidences of the following competing risks: transplantation, recovery, or decompensation on the waitlist. The cohort was stratified by cPRA partitions suggested by examination of cPRA as a continuous variable as described above. Competing risks analysis was then employed to measure the competing likelihoods of survival to transplantation, recovery, or death on the waitlist. Cumulative hazards for each waitlist outcome were measured by each cPRA group. Recovery was ascertained by removal from the waitlist due to a reason of transplantation no longer being required. Decompensation consisted of removal from the waitlist due to a reason of either death or decompensation that precluded transplantation. In the adjusted analysis, sub-distribution hazards models were fit to adjust for candidate-level factors associated with waitlist mortality: LAS at listing, gender, age at listing, primary diagnosis, need for ECMO at listing, need for mechanical ventilation at listing, and blood type. For candidates that survived to transplantation, post-transplant outcomes were measured. Overall survival from the time of transplantation was compared between these cohorts utilizing the Kaplan-Meier method and log-rank test. In the adjusted analysis, cox proportional hazards models were fit, employing the following donor-, transplant-, and recipient-related factors associated with post-transplant mortality in previously-reported SRTR data (9): ventilator at registration, primary diagnosis, gender, need for ECMO at registration, age, medical condition at the time of registration, ischemic time, donor gender, and donor age. Analyses were performed using R v3.4.1 (R Core Team, Vienna, Austria) with a p-value < 0.05 indicating statistical significance.

Results

Demographic Characteristics of Candidates

A total of 29,085 candidates met inclusion criteria for analysis. Of these, N= 23,562 (81 %) had no UA-HLA reported, while 5,523 (19%) reported UA-HLA data and as such had cPRA calculated as described in methods. For candidates with UA-HLA data available, unadjusted (univariate cox proportional hazards) and then adjusted (multivariable cox proportional hazards) models for the risk of waitlist mortality were constructed with cPRA treated as a restricted cubic spline. The relationship between listing cPRA and waitlist mortality is depicted in figure 2. While examination of cPRA as a restricted spline suggested increasing risk of waitlist mortality with an increase in cPRA in both the unadjusted and adjusted models, a hazard ratio of 1.0 remained in the 95% CI for all levels of cPRA. As such, the decision was made to partition candidates with UA-HLA reported into two cohorts of cPRA < 50 and cPRA ≥ 50 to permit categorical comparison with the control cohort and facilitate competing-risks analysis. This strategy yielded N=3,472 (62.8% of candidates with UA-HLA reported) with cPRA < 50, and N=2,051 with cPRA ≥ 50 (37.2% of candidates with UA-HLA reported).

Figure 2.

Examination of the relationship between waitlist mortality and candidate calculated Panel Reactive Antigen (cPRA), treated as a restricted cubic spline. The blue line (and blue shaded region) reflects the adjusted hazard of waitlist mortality (and 95% CI) by cPRA, treated as a restricted cubic spline. The gray line reflects the unadjusted univariate model for hazard of waitlist mortality (and 95% CI). Solid gray volume demonstrates the distribution of cPRA for candidates that reported UA-HLA. The hazard of waitlist mortality is increasing with higher cPRA.

Complete demographic data for the study population is reported in table 1. Candidates with the highest CPRA (≥50) were younger (mean 53.3 vs. 54.69 for CPRA < 50 and 54.0 years for no UA-HLA, P < 0.001), were more likely to be female (76.9% female vs 49.5% for CPRA < 50 and 41.2% for no UA-HLA, P < 0.001), were more likely to have a primary diagnosis of obstructive lung disease (32.7% vs 27.4% for CPRA < 50 and 29.4% for no UA-HLA, P < 0.001). There was no significant difference in the distribution of blood group, of need for ECMO or ventilator at the time of listing, or medical condition at the time of listing (all P > 0.05).

Table 1.

Demographic characteristics of candidates listed for lung transplantation, partitioned by calculated Panel Reactive Antigen.

	1 no cPRA	2 cPRA under 50	3 cPRA over 50	p
N	23562	3472	2051
Categorical cPRA (%)				<0.001
1 no cPRA	23562 (100.0)	0 (0.0)	0 (0.0)
2 cPRA under 50	0 (0.0)	3472 (100.0)	0 (0.0)
3 cPRA over 50	0 (0.0)	0 (0.0)	2051 (100.0)
Listing cPRA (mean (sd))	NaN	19(15)	75 (16)	<0.001
Waitlist outcome (%)				<0.001
Still waiting	1692 (7.2)	322 (9.3)	315 (15.4)
Died + too sick	3086(13.1)	399(11.5)	499 (24.3)
Recovery	315 (1.3)	48(1.4)	40 (2.0)
Transplanted	18469 (78.4)	2703 (77.9)	1197 (58.4)
Listing age (mean (sd))	54.08 (14.32)	54.69(13.63)	53.35(12.88)	0.003
Gender = M (%)	13850 (58.8)	1754 (50.5)	473 (23.1)	<0.001
FEV1 (mean (sd))	38.64 (20.79)	39.51 (20.81)	37.35 (20.18)	0.013
FVC (mean (sd))	48.29 (17.63)	49.01(17.33)	48.41(17.27)	0.148
Diagnostic Groups (%)				<0.001
A	6919 (29.4)	951 (27.4)	670 (32.7)
B	910 (3.9)	154 (4.4)	118 (5.8)
C	2862 (12.1)	393(11.3)	149 (7.3)
D	12871 (54.6)	1974 (56.9)	1114 (54.3)
Ethnicity (%)				<0.001
White	19275 (81.8)	2729 (78.6)	1610 (78.5)
Black	2004 (8.5)	407(11.7)	263 (12.8)
Hispanic	1655 (7.0)	233 (6.7)	125 (6.1)
Asian	453 (1.9)	73(2.1)	34 (1.7)
Amer Ind / Alaska Native	73 (0.3)	22 (0.6)	6 (0.3)
Native Hawaiian / Pacific Islander	23 (0.1)	2 (0.1)	3 (0.1)
Multiracial	79 (0.3)	6 (0.2)	10 (0.5)
BMI (mean (sd))	25.11 (4.69)	25.06 (4.66)	24.56 (4.54)	0.001
ABO (%)				0.766
A	9254 (39.2)	1364 (39.2)	813 (39.6)
AB	886 (3.8)	124 (3.6)	68 (3.3)
B	2627 (11.1)	386(11.1)	249(12.1)
O	10795 (45.8)	1598 (46.0)	921 (44.9)

Competing risks

Competing risks for transplantation, death or decompensation, or recovery were assessed at one year as described in methods. Candidates with CPRA ≥ 50 were the least likely to undergo transplantation, the most likely to still await transplantation and were the most likely to be removed from the waitlist due to death or decompensation. The respective incidence of transplantation for each group at one year was 71.9% for no UA-HLA, 69.5% for CPRA < 50, and 44.4%. For waitlist mortality, the incidence at one year was 10.9% for no UA-HLA, 8.8% for CPRA < 50, and 16.3% for CPRA ≥ 50 (P < 0.001 for each). Competing risks for transplantation, death or decompensation, and administrative censoring (still waiting) are represented in Figure 3. Assessment of the cumulative hazard for transplantation reflects an advantage for transplantation for the group with no UA-HLA reported (P < 0.001, Figure 4).

Figure 3.

Cumulative incidence curves for candidates awaiting lung transplantation, demonstrating the following competing risks: transplantation, death or decompensation, or recovery. Cohort is partitioned by calculated Panel Reactive Antigen. cPRA ≥ 50 was independently associated with increased waitlist mortality, decreased rate of transplantation and a longer waitlist time compared with cPRA < 50 and no UA-HLA candidates.

Figure 4.

Unadjusted cumulative hazard for transplantation for candidates listed for lung transplantation, stratified by candidate calculated Panel Reactive Antigen (cPRA). Patient with cPRA of 0 has a higher probability of being transplanted.

Adjusted analysis

We developed a sub-distribution hazard ratio model to consider cPRA in addition to other listing factors in order to measure the competing outcomes of waitlist mortality. On adjusted analysis, cPRA ≥50 was independently associated with increased waitlist mortality (HR 1.71, 95% CI 1.55–1.88, p < 0.001); Both listing diagnosis groups B (HR 2.15, 95% CI 1.86–2.49, p < 0.001); and D (HR 1.73, 95% CI 1.60–1.87, p < 0.001) were also associated with increased waitlist mortality while male gender was associated with reduced mortality (HR 0.70, 95% CI 0.66–0.76, p < 0.001); (Table 2).

Table 2.

Sub distribution Hazard model of waitlist mortality.

	Hazard Ratio	95% Cl	p-value
Sensitization
No UA-HLA Data Reported	Reference	Reference	Reference
CPRA < 50	0.84	0.756 to 0.933	0.001
CPRA ≥ 50	1.71	1.553 to 1.883	< 0.001
Gender
Female	Reference	Reference	Reference
Male	0.709	0.663 to 0.758	< 0.001
Age at Listing, by Year	0.999	0.993 to 1.006	0.086
LAS at Listing	1.02	1.015 to 1.026	< 0.001
Primary Diagnosis
Group A	Reference	Reference	Reference
Group B	2.151	1.861 to 2.487	< 0.001
Group C	1.197	1.041 to 1.375	0.011
Group D	1.732	1.601 to 1.874	< 0.001
ECMO at Registration	1.094	0.869 to 1.377	0.45
Ventilator at Registration	3.439	2.995 to 3.949	< 0.001
Blood Type
Type A	Reference	Reference	Reference
Type AB	0.994	0.832 to 1.187	0.94
Type B	1.136	1.022 to 1.261	0.18
Type O	1.122	1.048 to 1.202	0.001

Demographic characteristics of lung transplant recipients

Of the 29,085 candidates in the study cohort listed for transplantation, a total of 22,335 candidates were transplanted and had survival follow up; of these N= 18,436 (82.5 %) had no UA-HLA reported, N=2,703 (12.1%) had CPRA < 50, and N=1,196 had CPRA ≥ 50 (6.4%). Complete demographic data are reported in table 3. Recipients in the highest cPRA cohort tended to be younger (mean 53.4 years vs 54.9 for CPRA < 50 and 54.6 for no UA-HLA, P = 0.008), were more frequently female (72.2% vs 45.8% for CPRA < 50 and 38.3% for no UA-HLA, P < 0.001), and the primary diagnosis was more frequently obstructive lung disease (30.5% vs 26.5% for CPRA < 50 and 29.4% for no UA-HLA, P < 0.001). The LAS at the time of transplant did not differ significantly across cPRA levels (P = 0.305). Although the mean ischemic time was statistically greater for the cPRA>50 group, the clinical difference likely has no meaning (5.32 hours vs 5.22 for cPRA < 50 vs 5.17 for no UA-HLA; p=0.014). The cohort was equally distributed in regards to the need for ventilator or ECMO support at the time of transplant. Of these candidates that proceeded to transplantation, waitlist time was significantly greater for recipients with cPRA ≥ 50, with a mean waitlist time of 294 days vs 162 for cPRA < 50 vs 143 for no UA-HLA (P<0.001).

Table 3.

Demographic characteristics of recipients of lung transplantation, partitioned by calculated Panel Reactive Antigen.

	1 no cPRA	2 cPRA under 50	3 cPRA over 50	p
N	18436	2703	1196
Categorical.cpra (%)				<0.001
1 no cPRA	18436 (100.0)	0 (0.0)	0 (0.0)
2 cPRA under 50	0 (0.0)	2703 (100.0)	0 (0.0)
3 cPRA over 50	0 (0.0)	0 (0.0)	1196(100.0)
Listing cPRA (mean (sd))	N/A	19(15)	73 (15)	<0.001
Transplant type (%)				<0.001
Not reported	528 (2.9)	82 (3.0)	69 (5.8)
Double	12066 (65.4)	1947 (72.0)	833 (69.6)
Single	5842 (31.7)	674 (24.9)	294 (24.6)
Listing age (mean (sd))	54.58 (14.04	54.89 (13.70)	53.40(12.93)	0.008
Gender = M (%)	11366 (61.7)	1466 (54.2)	333 (27.8)	<0.001
FEV1 (mean (sd))	38.65 (20.78	39.51 (20.81)	37.35 (20.18)	0.013
FVC (mean (sd))	48.30 (17.62	49.01 (17.33)	48.41 (17.27)	0.16
Diagnostic Groups (%)				<0.001
A	5426 (29.4)	715 (26.5)	365 (30.5)
B	592 (3.2)	101 (3.7)	52 (4.3)
C	2241(12.2)	332 (12.3)	101 (8.4)
D	10177 (55.2)	1555 (57.5)	678 (56.7)
Ethnicity (%)				<0.001
White	15312 (83.1)	2177 (80.5)	965 (80.7)
Black	1504 (8.2)	288 (10.7)	136(11.4)
Hispanic	1199 (6.5)	162 (6.0)	69 (5.8)
Asian	298(1.6)	54 (2.0)	14 (1.2)
Amer Ind / Alaska Native	49 (0.3)	16 (0.6)	3 (0.3)
Native Hawaiian / Pacific Islander	18 (0.1)	1 (0.0)	0 (0.0)
Multiracial	56 (0.3)	5 (0.2)	9 (0.8)
BMI (mean (sd))	25.13 (4.68)	25.06 (4.66)	24.57 (4.54)	0.001
Ischemic time (mean (sd))	5.17 (1.75)	5.22(1.81)	5.32 (1.94)	0.014
Days on the waitlist (mean (sd))	143.26 (242.	162.38 (258.94)	293.69 (393.91)	<0.001
Listing LAS (mean (sd))	40.64 (15.78	38.40(17.80)	38.04 (16.66)	<0.001
Transplant LAS (mean (sd))	47.15 (17.69	47.47 (17.34)	47.86(17.29)	0.305
abo (%)				0.496
A	7413 (40.1)	1089 (40.3)	494 (41.4)
AB	715 (3.9)	101 (3.7)	40 (3.3)
B	2036(11.0)	299 (11.1)	135 (11.3)
O	8268 (44.8)	1214 (44.9)	527 (44.1)
Creatinine (mean (sd))	0.85 (0.41)	0.85 (0.34)	0.85 (0.61)	0.932
Ventilator at listing = 1 (%)	585 (3.2)	71 (2.6)	36 (3.0)	0.305
Ventilator at transplant = 1 (%)	1240 (6.9)	167 (6.4)	77 (6.8)	0.578
ECMO at listing = 1 (%)	257 (1.4)	40(1.5)	8 (0.7)	0.096
ECMO at transplant = 1 (%)	625 (3.5)	82 (3.1)	30 (2.7)	0.235
Donor
Age (mean (sd))	34.30 (14.18	34.72 (14.14)	34.89 (14.15)	0.17
Gender(%)				<0.001
Not reported	528 (2.9)	82 (3.0)	69 (5.8)
Female	7011 (38.0)	1074 (39.7)	543 (45.4)
Male	10897 (59.1)	1547 (57.2)	584 (48.8)
Ethnicity (%)				0.851
White	10978 (61.3)	1596 (60.9)	705 (62.6)
Black	3406(19.0)	522 (19.9)	204(18.1)
Hispanic	2755 (15.4)	384 (14.7)	175 (15.5)
Asian	489 (2.7)	77 (2.9)	31 (2.8)
Amer Ind / Alaska Native	86 (0.5)	13 (0.5)	5 (0.4)
Native Hawaiian / Pacific Islander	40 (0.2)	9 (0.3)	2 (0.2)
Multiracial	154 (0.9)	20 (0.8)	5 (0.4)
BMI (mean (sd))	25.93 (5.34)	26.15 (5.57)	26.23 (5.52)	0.039
Pa02 (mean (sd))	377.20(148.	377.13(146.39)	373.28 (148.03)	0.689
History of cigarette smoking (%)				<0.001
Not reported	529 (2.9)	82 (3.0)	69 (5.8)
No	16051 (87.1)	2354 (87.1)	1021 (85.4)
Unknown	189 (1.0)	32(1.2)	8 (0.7)
Yes	1667 (9.0)	235 (8.7)	98 (8.2)
LV EF% (mean (sd))	57.80 (12.20	58.15 (11.66)	57.49 (12.21)	0.274
Creatinine (mean (sd))	1.36(1.46)	1.39(1.49)	1.34(1.24)	0.47
Inotrop support (%)				<0.001
Not reported	537 (2.9)	82 (3.0)	69 (5.8)
No	8726 (47.3)	1344 (49.7)	553 (46.2)
Unknown	39 (0.2)	7 (0.3)	3 (0.3)
Yes	9134 (49.5)	1270 (47.0)	571 (47.7)
Vasodilator support (%)				<0.001
Not reported	536 (2.9)	82 (3.0)	69 (5.8)
No	14969 (81.2)	2228 (82.4)	962 (80.4)
Unknown	16 (0.1)	3 (0.1)	1 (0.1)
Yes	2915 (15.8)	390 (14.4)	164(13.7)
Pervious history of MI (%)				<0.001
Not reported	537 (2.9)	82 (3.0)	69 (5.8)
No	17498 (94.9)	2556 (94.6)	1098 (91.8)
Unknown	122 (0.7)	19 (0.7)	9 (0.8)
Yes	279 (1.5)	46(1.7)	20(1.7)
Pervious history of cancer (%)				<0.001
Not reported	531 (2.9)	82 (3.0)	69 (5.8)
No	17507 (95.0)	2560 (94.7)	1105 (92.4)
Unknown	65 (0.4)	12 (0.4)	4 (0.3)
Yes	333 (1.8)	49(1.8)	18(1.5)
Pervious history of cocaine use (%)				<0.001
Not reported	536 (2.9)	82 (3.0)	69 (5.8)
No	15277 (82.9)	2237 (82.8)	953 (79.7)
Unknown	284 (1.5)	35 (1.3)	21 (1.8)
Yes	2339(12.7)	349 (12.9)	153(12.8)
Post tranplant
Acute rejection (mean (sd))	2.84 (0.53)	2.86 (0.51)	2.84 (0.53)	0.333
Length of stay (mean (sd))	24.93 (29.00	24.29 (27.18)	25.80 (27.09)	0.32

The donors to the three groups were different in several parameters: the percentage of men was smaller as the cPRA increased (59.1 vs 57.2 vs 48.8; p < 0.001), there were fewer donors with a history of MI, CVA, cancer or use of cocaine as the cPRA increased, and less donors were on inotropes and vasodilators as the cPRA increased. Furthermore, patients with cPRA ≥ 50 had a longer waitlist time compared with cPRA < 50 and no cPRA patients (mean 293.69 days vs 162.38 and 143.26 days, respectively, p < 0.001) (Table 3).

Relationship between cPRA and post-transplant outcomes

Once transplanted, post-transplant survival was similar among the cohorts (Figure 5). A Cox regression model for mortality post-transplant indicated that male gender, diagnosis group D (restrictive lung disease) and need for invasive mechanical ventilation pre-transplant were all associated with an increased hazard of post-transplant mortality. Higher listing cPRA was not associated with an increased hazard of post-transplant mortality (Figure 6).

Figure 5.

10-year unadjusted Kaplan-Meier estimate of survival of recipients following lung transplantation, stratified by calculated Panel Reactive Antigen (cPRA), no difference was found between the different cPRA groups.

Figure 6.

Cox regression model for mortality post-transplant. High calculated Panel Reactive Antigen was not found to be a risk factor for reduced survival post-transplant.

Discussion

In this large retrospective study using the UNOS database we demonstrate that sensitized lung transplant candidates (those with a higher degree of unacceptable HLA antigens, and therefore elevated cPRA) experience longer waitlist times, lower rates of transplantation, and higher rates of waitlist mortality than candidates with lower cPRA or without any unacceptable HLA antigens. While listing centers may differ in their screening for and consideration of HLA antigens, this work describes for the first time the subsequent waitlist outcomes in a nationally-representative cohort. These data emphasize the degree to which the sensitized candidate is at a disadvantage in the current lung allocation system in the United States. Importantly, once transplanted the long-term survival of these recipients was similar to other lung transplant recipients. We were able to quantify the magnitude of the cPRA effect on lung transplant candidates, but further evaluation of allocating organs with consideration of candidate cPRA may be warranted in order to optimize equity in access to transplants.

Specific HLA Ab compatibility is a primary matching criterion in all solid-organ transplantation, and previous studies in lung transplant candidates have suggested that the use of a virtual crossmatch can decrease the need for traditional crossmatch and through broader availability of suitable allografts decrease waiting list time and mortality rates for candidates with HLA-specific antigens (10). Going a step further, kidney organ allocation takes under consideration highly-sensitized renal transplant candidates by using cPRA as a reference point (in order to try and reduce the kidney offers declined and enable more transplants to sensitized patients). However, this is not the situation for lung transplant candidates, where no consideration for highly sensitized patients occurs in the latest allocation scheme that dealt with the DSA designation (11). It is important to emphasize that despite these findings, we found that once transplanted, highly sensitized recipients experience similar survival rates to unsensitized lung transplant candidates. Our findings are in partial agreement with Hayes et. al. as he found that pre-transplant class I and II PRA levels > 0 were not associated with mortality or acute rejection in pediatric LTx recipients. In contradistinction, Hayes et. al did find that in adult CF pre-transplant PRA class II >10 %, but not class I is associated with elevated mortality hazard after LTx (12,13). Furthermore, Shah et.al., in a retrospective analysis of the UNOS database between 1987–2005 found that PRA level exceeding 25% is associated with an increased hazard of mortality. However, a later cohort of the same data base (1998–2005) revealed no difference in survival; Whether advanced immunological tools, better organ allocation or different induction or desensitization protocols are responsible for that still remains unknown (14).

Indeed, since the Lung Allocation Score (LAS) was implemented in 2005, lung transplant in the U.S. has experienced tremendous change. The application of the LAS score resulted in more transplants, decreased the time on the waitlist and wait list mortality, and increased post-transplant survival (15). However, some transplant professionals and patients’ groups highlight that certain subsets of patients, such as the highly sensitized candidate, may present special circumstances that are not currently addressed by the allocation system. Importantly, the data presented in the current study emphasize that the highly sensitized patients suffer worse outcomes due to increased waitlist times and decreased waitlist survival, but not due to a decrement in posttransplant survival. These data indicated that certain modifications to the allocation system may represent a modifiable condition improving the broader care of the transplant candidate from the time of listing.

The importance of specific antibodies against HLA has been well-established as the methods evolved through the years allowing for increased sensitivity to detect specific antibodies. It is believed that avoiding donor specific antibodies can help prevent antibody mediated rejection (AMR), which can be a fulminant form of lung rejection and increases the risk of developing chronic lung allograft dysfunction (CLAD) (16–18). HLA mismatching was found to be associated with increased hazard risk for death following lung transplant (19), and attempts to increase the lung donor pool by reducing the patient cPRA using desensitization protocols, and by that effect the patient survival post-transplant, were unsuccessful (20). In 2009 the cPRA was introduced into renal transplantation; the system calculating the cPRA was using an established formula, the unacceptable HLA values that have been entered for the candidate and HLA frequencies derived from the HLA types found in more than 12,000 donors. In renal transplant, using cPRA in organ allocation caused a decrease of 83% in the number of kidneys offers declined nationwide due to a positive crossmatch and thus enabling more transplants to sensitized patients (21).

In 2010, the Canadian Cardiac Transplant Network (CCTN) created a unique status listing for highly sensitized heart transplant candidates; Status 4S listing required a cPRA >80% and thus enabled geographic expansion of the donor pool for this subset of candidates. This change produced acceptable short-term survival, freedom from CAV and low rates of clinically relevant AMR, however, it caused a significantly higher rates of cellular rejection and de novo donor-specific antibody development in this population, which may translate into reduced long-term survival (22). Furthermore, a recent study reviewing the Canadian data base pointed out that despite the 4S unique criteria for highly sensitized patients these patients still experience extended waiting times (23). Importantly, recently Kransdorf et. al. had similar findings to ours using the UNOS database; They demonstrated that highly sensitized patients pre-heart transplant experience increased death and wait times on the waitlist, nonetheless they did find different post-transplant survival for those patients (in contrary to our findings in lung transplant patients), thus changing the allocation for these heart transplant candidates may be more complex than for lung transplant candidates (8). Finally, in a recent single center study by Tague et. al. in lung transplant candidates increasing cPRA was associated with longer waiting times, an increased risk of death and a decreased likelihood of transplantation, similar to the results that we have demonstrated using a national dataset (4).

One should keep in mind this study limitations; as this study data origin is the USA, it may be most relevant to transplant settings with similar donor, recipient, and operative characteristics. Moreover, as with all retrospective studies, there exists the possibility of potential unmeasured confounders for which we cannot account. Furthermore, we have analyzed only the patients for whom the data regarding the cPRA and survival was available, and we are unable to consider changes in the cPRA along the period the patient was on the waitlist nor changes in the LAS while on the list. Finally, center variability in determining and listing unacceptable antigens in UNET can vary. Some centers do not list all unacceptable antigens or list only those over a certain MFI in an attempt to maximize the number of organ offers. However, despite that limitation, it is clear from this work that candidates with unacceptable antigens listed in the national lung matching program are disadvantaged and are more likely to die without transplant than those patients without unacceptable antigens.

In summary, candidates for lung transplantation with cPRA ≥50 are significantly disadvantaged in lung transplantation with respect to rates of transplantation and waitlist mortality with a nearly 1.7-fold increase in the risk of dying while waiting for an acceptable lung allograft without adversely impacting posttransplant survival. Recent changes to the lung allocation system in the U.S. have occurred that are related to regional allocation and it is unclear if that will impact this finding, but the changes do not include any special considerations for sensitized patients. Importantly, the elevated cPRA does not correlate with a decrease in the posttransplant survival of these patients following lung transplantation. Therefore, we suggest that future re-evaluation of lung allocation system should consider methods that increase equality of organ allocation by increasing transplantation rates and reducing waitlist mortality for highly sensitized patients listed for lung transplantation.