Abstract
Rationale: There is significant variation in approach to pre–lung transplant donor-specific antibodies (DSA), with some centers declining to cross any DSA. We implemented a protocol for transplantation for candidates with pretransplant DSA so long as a prospective complement-dependent cytotoxicity crossmatch was negative, regardless of number, specificity, class, or mean fluorescence intensity.
Objectives: To compare post-transplant outcomes including overall survival, chronic lung allograft dysfunction–free survival, antibody-mediated rejection, and acute cellular rejection in lung transplant recipients where pretransplant DSA was and was not present.
Methods: This was a single-center retrospective cohort study. For recipients with pretransplant DSA, if the prospective complement-dependent cytotoxicity crossmatch was negative, the donor offer was accepted and plasmapheresis was performed within 24 hours of transplantation and continued until retrospective crossmatch results returned. Immunosuppression and post-transplant management were not otherwise modified.
Results: Of the 203 included recipients, 18 (8.9%) had pretransplant DSA. The median DSA mean fluorescence intensity was 4,000 (interquartile range, 2,975–5,625; total range, 2,100–17,000). The median number of DSA present per patient was one (interquartile range, 1–2). The presence of pretransplant DSA was not associated with increased mortality (hazard ratio, 1.2; 95% confidence interval [CI], 0.4–3.4) or decreased chronic lung allograft dysfunction–free survival (hazard ratio, 1.1; 95% CI, 0.6–2.1). Recipients with pretransplant DSA were more likely to require prolonged mechanical ventilation (adjusted odds ratio, 7.0; 95% CI, 2.3–21.6) and to have antibody-mediated rejection requiring treatment (adjusted odds ratio, 7.5; 95% CI, 1.0–55.8).
Conclusions: A protocol of accepting donor offers for lung transplant candidates with preformed, complement-dependent cytotoxicity crossmatch-negative DSA is associated with increased need for prolonged mechanical ventilation and antibody-mediated rejection without affecting short-term overall or chronic lung allograft dysfunction–free survival.
Keywords: antibody-mediated rejection, chronic lung allograft dysfunction, donor-specific antibodies, lung transplantation
Despite consensus guidelines, there is significant center-to-center variation in approaches to pre–lung transplant HLA antibodies (1, 2). In addition to differences in testing technique, such as the use of prescreening versus single antigen beads, there is variability in the mean fluorescence intensity (MFI) threshold used to define antibodies as present and in the frequency of screening (3). Programs also differ significantly in their willingness to cross donor directed antibodies at the time of transplant. Some centers do not cross any preformed donor-specific antibodies (DSA) as predicted by a virtual crossmatch (4). Others cross based on factors including the specificity, MFI, titer, and C1q binding of the antibody and the ability of the potential recipient to tolerate augmented immunosuppression (5, 6).
Almost all contemporary data on the adverse impact of DSA on survival and graft function, however, come from studies of post-transplant de novo DSA (7, 8). Experience with a more open approach to pretransplant DSA has primarily been limited to candidates who can tolerate augmented immunosuppression with antithymocyte globulin (ATG), intravenous immunoglobulin (IVIG), and plasmapheresis (9). Here we report our experience with a protocol whereby donor offers were accepted for candidates with preformed DSA in the setting of a negative prospective complement-dependent cytotoxicity (CDC) crossmatch, regardless of number, specificity, class, or MFI. The objective of this paper was to compare post-transplant outcomes including overall survival, chronic lung allograft dysfunction (CLAD)-free survival, antibody-mediated rejection (AMR), and acute cellular rejection (ACR) in lung transplant recipients where pretransplant DSA was and was not present.
Methods
Study Cohort
This was a single center retrospective cohort study of all adult lung transplant recipients at Brigham and Women's Hospital (BWH) from October 1, 2012, to February 28, 2018. Transplant candidates were tested for A, B, DQ, and DR HLA antibodies with LABscreen Mixed Product (One Lambda). Samples with a positive prescreen, defined as a normalized background ratio of greater than 2.5 for class I antibodies and greater than 2.0 for class II antibodies, were then analyzed with the LABscreen single antigen assay (One Lambda). The assay was considered positive for class I antibodies if any bead for a given antigen was detected at MFI greater than 1,000 and was considered positive for class II antibodies if at least 60% of the beads for a given antigen were detected at MFI greater than 1,000. Sensitized candidates were screened monthly for 3 months and then every 3 months thereafter in the absence of a new sensitizing exposure. Nonsensitized candidates were screened every 3 months.
Starting October 1, 2012, no unacceptable antigens were listed in the United Network of Organ Sharing. Any HLA present on the most recent candidate serum sample before the donor offer and any HLA present on two or more candidate serum samples obtained at any time before transplant, were considered preformed DSA for the purpose of organ offer assessment. For sensitized patients, when able, blood samples were sent to local and regional organ procurement organizations updated every 3 months in the absence of a new sensitizing exposure. Some organ procurement organizations were also able to send donor blood to our local organ procurement organizations in advance of transplant acceptance. At the time of a donor offer, a prospective CDC crossmatch was performed for any candidate with preformed antibodies against donor HLA (Figure 1). Transplant was not pursued for these recipients if the CDC crossmatch was positive or could not be performed.
Figure 1.
Clinical management algorithm of lung transplant recipients with and without preformed donor-specific antibodies (DSAs) at the time of transplant offer. Historical DSA defined as donor-directed HLA antibody found on two or more pretransplant screens. CDC-XM = complement-dependent cytotoxic crossmatch; HLA = human leukocyte antigen.
If the prospective CDC crossmatch was negative, the donor offer was accepted. Recipients with pretransplant DSA had a session of plasmapheresis on intensive care unit arrival. Plasmapheresis was continued every other day until retrospective flow crossmatch returned. If the retrospective crossmatch was positive and there was allograft dysfunction concerning for AMR, plasmapharesis was continued to complete three additional sessions. IVIG and rituximab were administered for recipients with ongoing allograft dysfunction, defined as persistent hypoxemia and/or need for mechanical ventilation.
All recipients underwent solumedrol and anti-thymoctyte (until March 11, 2014) or basiliximab (after March 11, 2014) induction. All recipients were maintained on a combination of a calcinurin inhibitor (most commonly tacrolimus), a cell cycle inhibitor (most commonly mycophenolate mofetil), and prednisone. Bronchoscopy with transbronchial biopsies was performed for surveillance at 1, 3, 6, and 12 months and for cause with change in allograft function. Post-transplant DSA were only checked when clinically indicated (e.g., decline in spirometry, unexplained hypoxemia, diffuse alveolar hemorrhage, or sensitizing exposure) and not for routine screening.
Subject Characteristics and Outcomes
All transplant recipients with preformed DSA (based on prior screens) at the time of transplant were identified. Recipients were further categorized as those with and without a historical DSA or DSA on the most recent pretransplant screen. In addition to basic sociodemographic and clinical data, such as native lung disease, lung allocation score at transplant, and waitlist time, we also identified the number, class, and MFI of the antibodies present.
The primary study outcomes were overall and CLAD-free survival among patients who did and did not have pretransplant DSA. CLAD was characterized according to consensus definitions and divided into bronchiolitis obliterans syndrome and restrictive allograft syndrome (10). Secondary study outcomes included initial duration of mechanical ventilation greater than 5 days, length of initial hospitalization, ACR score (defined as the sum of the A grades on each biopsy divided by the total number of biopsies), freedom from ACR, and AMR requiring treatment (11). AMR requiring treatment was defined as probable or definitive AMR according to consensus guidelines. Treatment included antibody-directed therapy, such as IVIG, plasmapheresis, and/or rituximab (12). In a post hoc analysis we compared these outcomes between recipients with pretransplant DSA MFI greater than 5,000 and those 1,000–5,000.
Statistical Analysis
Basic clinical and sociodemographic characteristics were captured descriptively, with means and standard deviations for normally distributed variables and medians and interquartile ranges (IQR) for nonnormally distributed variables. We compared clinical and sociodemographic characteristics between recipients with and without preformed DSA using Student’s t test, Fisher exact tests, and Wilcoxon rank sum, where appropriate. We used Cox proportional hazards models to compare the time-dependent outcomes (survival, freedom from CLAD, and freedom from ACR) between patients with and without preformed DSA, first treated as a single variable, then with other known covariates associated with these outcomes. We used logistic regression models for the outcomes mechanical ventilation greater than 5 days and AMR requiring treatment with presence of pretransplant DSA as our predictor, adjusting for clinical and sociodemographic variables that have been associated with primary graft dysfunction (for the outcome mechanical ventilation >5 d) and AMR. Type of induction (ATG vs. basiliximab) was included in all models. The institutional review board at BWH approved this study (2017P002285).
Results
Study Cohort
Between October 1, 2012, and February 28, 2018, 203 patients underwent lung transplantation. Demographic and clinical characteristics of the study cohort are presented in Table 1. The median overall follow-up time was 1.4 years (IQR, 0.6–2.8 yr). Among all recipients, 71 (35.0%) had any HLA antibody detected before transplant, most of which were class I. Of patients with HLA antibodies pretransplant, 23 (32.4%) had at least one prospective CDC crossmatch performed before transplant. The median number of crossmatches per patient was one (IQR, 1–4) and six (26.1%) patients had at least one positive crossmatch. Of the 62 total crossmatches performed, 14 (22.6%) were positive. Of the 54 candidates who died or become too sick for transplant during the study period, only four were sensitized (panel reactive antibody of 71%, 95%, 98%, and 99%) and a prospective crossmatch negative donor did not become available.
Table 1.
Clinical and sociodemographic characteristics of study cohort (n = 203)
| Age, median (range), yr | 61 (52–66) |
| Female, n (%) | 83 (40.9) |
| Hispanic or nonwhite race or ethnicity, n (%) | 24 (11.8) |
| Native disease, n (%) | |
| Pulmonary fibrosis | 120 (59.1) |
| Obstructive lung disease | 37 (18.2) |
| Cystic fibrosis | 26 (12.8) |
| Other | 20 (9.8) |
| Time on wait list at transplantation, median (range), d | 178 (48–372) |
| Lung allocation score, median (range) | 41.4 (34.5–52.5) |
| Any human leukocyte antibodies at transplant, n (%) | 71 (35.0) |
| Class I | 44 (62.0) |
| Class II | 9 (12.7) |
| Class I and II | 18 (25.3) |
| DSA at transplant, n (%) | 18 (8.9) |
| Historical only* | 12 (66.6) |
| Historical and current† | 6 (33.3) |
| Bilateral transplant, n (%) | 139 (68.5) |
| Cardiopulmonary bypass, n (%) | 169 (83.3) |
| Cytomegalovirus donor positive/recipient negative, n (%) | 55 (27.1) |
| Length of initial hospitalization, median (range) (d) | 19 (14–29) |
| Died during the first year, n (%) | 18 (8.9) |
| One or more episodes of acute cellular rejection, n (%) | 96 (49.5) |
| Developed chronic lung allograft dysfunction, n (%) | 46 (22.7) |
| Died, n (%) | 33 (16.2) |
Definition of abbreviations: DSA = donor-specific antibodies; HLA = human leukocyte antigen.
Historical DSA only defined as any HLA present on two or more candidate serum samples obtained at any time before transplant but not on the most recent serum sample available.
Historical and current DSA defined as any HLA present on two or more candidate serum samples obtained at any time before transplant and on the most recent serum sample available.
DSA Characteristics
At the time of transplant, 18 (8.9%) recipients had pretransplant DSA, 12 of which were only present on historical pretransplant screens and 6 of which were present on historical and the most recent pretransplant screen. The median DSA MFI was 4,000 (IQR, 2,975–5,625; total range 2,100–17,000). The median number of DSA present per patient was one (IQR, 1–2; total range, 1–3). Of the six recipients with a DSA present on the most recent pretransplant screen, five underwent postoperative plasmapheresis and one did not because of significant bleeding. Of the 12 recipients with historical DSA, only 4 underwent plasmapharesis. Three did not undergo plasmapharesis because of bleeding (including one case of disseminated intravascular coagulation and two cases of bleeding through chest tubes from the thorax). The remainder did not based on a decision at the time of transplant that plasmapheresis was not necessary, either because the DSA was very remote and/or relatively low MFI.
Recipients with Pretransplant DSA
Recipients with pretransplant DSA were more likely to be nonwhite or Hispanic (27.8% vs. 10.3%; P = 0.05). They also had a higher lung allocation score at the time of transplant (median, 47.7 vs. 41.2; P = 0.03) (Table 2). There were no significant differences in sex, native lung disease, wait time, bilateral transplant, or length of follow-up time between the two groups. Among recipients with pretransplant DSA, 11 (61.1%) had follow-up longer than 1.4 years and 6 (33.3%) had more than 3 years of follow-up. Recipients with pretransplant DSA were more likely to have a positive retrospective B-cell crossmatch (33.3% vs. 13.9%; P = 0.04) but not a positive retrospective T-cell crossmatch. The identity and MFI of each recipient’s pretransplant DSA are listed in Table 3.
Table 2.
Lung transplant recipients with and without preformed DSA at the time of transplant (n = 203)
| No Pretransplant DSA (n = 185) | Pretransplant DSA (n = 18) | |
|---|---|---|
| Age, median (range), yr | 62 (53–67) | 57 (46–65) |
| Female, n (%) | 73 (39.5) | 10 (55.6) |
| Hispanic or nonwhite race or ethnicity, n (%) | 19 (10.3) | 5 (27.8) |
| Pulmonary fibrosis, n (%) | 108 (58.4) | 12 (66.7) |
| Wait time, median (range), d | 178 (48–355) | 234 (123–487) |
| Lung allocation score, median (range) | 41.2 (34.1–51.6) | 47.7 (39.1–76.7) |
| Longest ischemic time, min, ± standard deviation | 297 ± 90 | 286 ± 79 |
| Cytomegalovirus donor positive recipient negative, n (%) | 49 (26.5) | 6 (33.3) |
| Bilateral transplant, n (%) | 124 (67.0) | 15 (83.3) |
| Positive T-cell retrospective flow crossmatch, n (%) | 16 (8.8) | 3 (16.7) |
| Positive B-cell retrospective flow crossmatch, n (%) | 25 (13.9) | 6 (33.3) |
| Follow-up time, median (range), yr | 1.4 (0.7–2.8) | 1.8 (0.7–4.3) |
| >3 yr follow-up time, n (%) | 40 (21.6) | 6 (33.3) |
| One or more episodes of acute cellular rejection, n (%) | 90 (51.1) | 6 (33.3) |
| Develop chronic lung allograft dysfunction, n (%) | 40 (21.6) | 6 (33.3) |
| Died, n (%) | 29 (15.7) | 4 (22.2) |
Definition of abbreviation: DSA = donor-specific antibodies.
Table 3.
Characteristics of DSA present at the time of transplant (n = 18)
| Recipient | Historical DSA | Peak Historical MFI | Current DSA | MFI at Transplant |
|---|---|---|---|---|
| 1 | A29 | 4,800 | A29 | 4,000–5,000 |
| DR4 | 3,800 | DR4 | 1,200–3,800 | |
| 2 | A68 | 5,200 | A68 | 1,830–5,290 |
| 3 | DR13 | 7,200 | DR13 | 3,300–4,600 |
| 4 | A2 | 5,600 | A2 | 3,100–3,600 |
| 5 | A24 | 17,000 | A24 | 3,000–12,500 |
| A25 | 16,000 | A25 | 14,900 | |
| 6 | A2 | 4,500 | A2 | 1,875–3,000 |
| 7 | DQ7 | 5,700 | — | — |
| 8 | DQ7 | 1,800 | — | — |
| DR11 | 2,250 | |||
| DR12 | 2,250 | |||
| 9 | A3 | 2,600 | — | — |
| 10 | DR17 | 2,310 | — | — |
| 11 | A2 | 3,400 | — | — |
| 12 | A1 | 5,800 | — | — |
| 13 | B44 | 6,300 | — | — |
| DR1 | 3,290 | |||
| 14 | DR52 | 3,100 | — | — |
| 15 | DR4 | 4,000 | — | — |
| 16 | A23 | 3,900 | — | — |
| 17 | A2 | 2,100 | — | — |
| 18 | DR17 | 4,000 | — | — |
| DR52 | 4,200 |
Definition of abbreviations: DSA = donor-specific antibodies; MFI = mean fluorescence intensity.
Overall and CLAD-free Survival
The presence of pretransplant DSA was not associated with worse survival on bivariate analysis (hazard ratio [HR], 1.2; 95% confidence interval [CI], 0.4–3.6) or after adjusting for age, lung allocation score, bilateral transplant, ATG induction, or native lung disease (HR, 1.2; 95% CI, 0.4–3.6) (Figure 2A). These results were not impacted by whether the DSA was present on the most recent screen before transplant or a historical DSA only. The 1-year survival was 88.9% among the recipients with pretransplant DSA and 91.3% among recipients without DSA. None of the six recipients with a DSA present on the most recent pretransplant screen died during the study follow-up period.
Figure 2.
Differences in (A) overall survival, (B) chronic lung allograft dysfunction (CLAD)-free survival, and (C) grade 2 or 3 CLAD-free survival between recipients with and without pretransplant donor-specific antibodies. DSA = donor-specific antibodies.
The presence of pretransplant DSA was not associated with worse CLAD-free survival on bivariate analysis (HR, 1.0; 95% CI, 0.5–2.2) or after adjusting for age, lung allocation score, ATG induction, bilateral transplant, cytomegalovirus mismatch status, ACR score, or native lung disease (HR, 1.0; 95% CI, 0.5–2.3) (Figure 2B). The presence of pretransplant DSA was not associated with grade 2 or 3 CLAD-free survival on bivariate (HR, 0.8; 95% CI, 0.3–2.3) or adjusted analysis (HR, 0.7; 95% CI, 0.2–2.2) (Figure 2C). Among the 46 recipients with at least 3 years follow-up (40 [21.6%] without pretransplant DSA and 6 [33.3%] with pretransplant DSA), there were 2 deaths and 21 CLAD events. There were no differences in CLAD-free survival on bivariate (HR, 0.7; 95% CI, 0.3–1.7) or adjusted analysis (HR, 0.8; 95% CI, 0.3–2.1) between the two groups.
None of the six recipients with a DSA present on the most recent pretransplant screen developed grade 2 or 3 CLAD. Of the five recipients who developed restrictive allograft syndrome, only one had preformed DSA, which was not present on the most recent pretransplant screen. Recipients with pretransplant DSA who underwent plasmapharesis did not have improved CLAD-free survival compared with those who did not (HR, 0.7; 95% CI, 0.2–3.0).
Secondary Outcomes
Recipients with pretransplant DSA were more likely to require mechanical ventilation for longer than 5 days even after adjusting for pretransplant mechanical ventilation, age, ethnicity, sex, native lung disease, ischemic time, and bilateral transplant status (odds ratio [OR], 7.0; 95% CI, 2.3–21.6) (Table 4). They also had a significantly longer index hospitalization (median, 32 vs. 18 d; P = 0.05). Recipients with a positive retrospective B- or T-cell crossmatch were not more likely to require mechanical ventilation for more than 5 days (P = 0.25) or to have a significantly longer hospitalization (P = 0.66).
Table 4.
Impact of pretransplant DSA on additional post-transplant outcomes
| Outcome | 95% CI | |
|---|---|---|
| Mechanical ventilation >5 d* | OR, 7.2 | 2.3–21.5 |
| Freedom from any ACR† | HR, 0.5 | 0.2–1.1 |
| Freedom from ACR grade 2 or higher† | HR, 0.6 | 0.2–1.9 |
| De novo DSA‡ | OR, 0.8 | 0.1–7.7 |
| AMR requiring treatment§ | OR, 7.5 | 1.0–55.8 |
Definition of abbreviations: ACR = acute cellular rejection; AMR = antibody-mediated rejection; CI = confidence interval; DSA = donor-specific antibodies; HR = hazard ratio; OR = odds ratio.
Adjusted for pretransplant mechanical ventilation, age, ethnicity, sex, native lung disease, ischemic time, and bilateral transplant status.
Out of 195 recipients who underwent biopsy; adjusted for age, native lung disease, bilateral transplant, and cytomegalovirus mismatch status.
Out of 130 recipients screened for DSA; adjusted for sex, age, and ethnicity.
Out of 130 recipients screened for DSA and assessed for AMR; adjusted for sex, age, and the presence of pretransplant non-DSA HLA antibodies.
There was no association between pretransplant DSA and ACR score (average score, 0.17 vs. 0.29; P = 0.25). Pretransplant DSA was not associated with time to ACR of any grade (HR, 0.5; 95% CI, 0.2–1.1) on bivariate analysis or after adjusting for age, native lung disease, ATG induction, bilateral transplant, or cytomegalovirus mismatch status (HR, 0.5; 95% CI, 0.2–1.1). Pretransplant DSA was not associated with time to ACR grade 2 or higher (HR, 0.5; 95% CI, 0.2–1.7) on bivariate analysis or after adjusting for the same factors (HR, 0.6; 95% CI, 0.2–1.9).
Among the study cohort, 130 (64.3%) recipients had clinically indicated screens for post-transplant DSA and 11 (8.4%) had DSA detected. Of recipients with post-transplant DSA, three were persistent from pretransplant and eight were de novo. Most pretransplant DSA (71.4%) were not detected post-transplant. AMR requiring treatment occurred in three (16.7%) recipients with pretransplant DSA and six (3.2%) recipients without pretransplant DSA. Recipients with pretransplant DSA more likely have AMR requiring treatment (OR, 5.0; 95% CI, 1.1–22.8), an effect that persisted after adjusting for sex, age, and the presence of pretransplant non-DSA HLA antibodies (OR, 7.5; 95% CI, 1.0–55.8). All cases of post-transplant AMR among recipients with pretransplant DSA occurred in patients with historical rather than current, prospective crossmatch-negative DSA. All three of the recipients with AMR and pretransplant DSA had clearance of DSA following treatment; however, two developed CLAD within a year after AMR and one died of pneumonia following augmented immunosuppression (see Table E1 in the online supplement). There were no cases of AMR in recipients with a positive retrospective B- or T-cell crossmatch but no pretransplant DSA. Recipients with pretransplant DSA who underwent plasmapharesis did not have reduced AMR requiring treatment compared with those who do not undergo plasmapheresis (OR, 1.7; 95% CI, 0.1–24.2).
None of the patients with pretransplant DSA MFI greater than 5,000 died during study follow-up. There was no difference in CLAD-free survival between recipients with DSA MFI greater than 5,000 and 1,000–5,000 (HR, 1.1; 95% CI, 0.1–8.1). None of the recipients with DSA greater than 5,000 developed CLAD 2 or 3 and there was no difference in post-transplant AMR or ACR score between the two groups.
Discussion
In this study, we report our experience with a protocol whereby donor offers were accepted for lung transplant candidates with preformed DSA but a negative prospective CDC crossmatch. This approach was associated with increased duration of mechanical ventilation, longer index hospitalization, and increased AMR but no effect on ACR or overall or CLAD-free survival.
The prevalence of pretransplant recipients with HLA antibodies in our cohort was consistent with the available literature, which ranges from 10.8 to 42.9% depending on the population and screening technique (4, 7, 13). The 8.9% prevalence of pretransplant DSA is also consistent with the results of a recent metaanalysis, where the prevalence was 5.7% over approximately 2,800 transplants (3). Because our center uses prescreen followed by single antigen testing to define HLA antibodies as being present, it is likely that we crossed some DSA that would have been detected on single antigen testing or that would have been identified in a center using a lower MFI threshold (14). The impact of DSA antibodies present on single antigen testing but not on prescreen is unknown. As noted in other studies, MFI was not directly related to a positive prospective CDC crossmatch (15). Candidates with MFI greater than 10,000 had negative prospective CDC crossmatches and candidates with MFI 3,000–5,000 had positive prospective crossmatches. Our study points to the need for additional in vivo data on the sensitivity and specificity of specific DSA and/or DSA characteristics, such as MFI, complement fixation, or immunoglobulin subtype, for a cytotoxic crossmatch.
Pretransplant DSA was not associated with ACR, both as a time-dependent outcome and adjusted for the number of post-transplant biopsies (ACR score), or with survival or CLAD-free survival in our cohort. Tinckam and coworkers (9) similarly found no increase in ACR after crossing pretransplant DSA (including cytotoxic DSA) although their protocol included ATG, intraoperative plasma exchange, and IVIG. They also reported no difference in graft survival. Our results may indicate that a similar outcome could be achieved without augmented immunosuppression in the perioperative period, although at the risk of higher rates of prolonged mechanical ventilation and AMR. Given the small number of recipients with pretransplant DSA, the confidence bounds do not exclude the possibility of harm regarding overall and CLAD-free survival. In addition, because not all recipients received immediate postoperative plasmapheresis, it is possible that stricter adherence to our protocol would have improved the rates of subsequent early graft dysfunction and/or AMR.
Although we did not have data on primary graft dysfunction, the need for prolonged (>5 d) mechanical ventilation among recipients with pretransplant DSA may suggest a higher rate of severe primary graft dysfunction in this population. Given that prolonged mechanical ventilation was not more common in recipients with a positive retrospective flow crossmatch but no pretransplant DSA, it is possible that the pretransplant DSA played a role in the need for longer support. Most patients improved and were ultimately discharged without requiring antibody-directed treatment. Subsequent AMR was, however, more common in recipients with pretransplant DSA, particularly those with historical DSA that was not present on the most recent pretransplant HLA antibody screen. Despite this finding, DSA cleared with antibody-directed treatment, although one patient died from infection following the augmented immunosuppression. The recurrence of pretransplant DSA has also been reported by Roux and coworkers (6), where pretransplant DSA was associated with both post-transplant DSA and AMR. This may indicate a memory response with subsequent allograft impairment (16).
Close monitoring for rising DSA MFI and/or allograft dysfunction may be warranted in recipients with pretransplant DSA to identify early signs of AMR or to trigger DSA treatment (17). Because we do not routinely screen for post-transplant DSA (only when there is a clinical indication) we do not know whether trending DSA at scheduled intervals might identify a point of intervention before the development of AMR. We also do not know whether following other markers of allograft injury that may precede AMR, such as donor cell-free DNA, might be of particular benefit in recipients with pretransplant DSA (18). The decision to cross a historical DSA, however, should take into account other risk factors for poor tolerance of AMR treatment, including older age or chronic respiratory infections (9), and likelihood of tolerating plasmapheresis/bleeding risk.
There are several approaches to management of sensitized patients with advanced lung disease, ranging from avoidance of transplant for patients with a calculated panel reactive antibody above a certain threshold, to such strategies as pretransplant HLA antibody treatment, an approach that has limited efficacy (19). Other options include only crossing pretransplant antibodies with an MFI below a certain threshold or crossing antibodies regardless of MFI or cytotoxicity if the recipient can tolerate ATG induction immunosuppression and plasmapharesis/IVIG (9). These decisions must also be balanced against the risk of death on the waiting list for sensitized candidates if DSA are completely avoided, which is not insubstantial (20). In our study cohort, willingness to accept donor offers, even in the presence of high MFI or multiple DSA, so long as a prospective CDC crossmatch was negative, was not associated with adverse short-term post-transplant survival. Long-term follow-up, however, is needed, as are additional studies assessing the characteristics of DSA most predictive of negative post-transplant outcomes.
Limitations
Our study has several additional limitations. First, despite the overall size of the cohort, only 18 recipients had pretransplant DSA, limiting our ability to detect small effect sizes. It is reassuring, however, that we did not see a trend toward decreased survival or CLAD-free survival, although we cannot exclude the possibility of harm. Second, our median follow-up time was relatively short and, although we did not observe any early effects of pretransplant DSA, these may not be apparent until the follow-up period is longer. Among recipients with more than 3 years of follow-up, however, we did not see a trend toward decreased CLAD-free survival. Finally, we did not routinely screen for C or DP group HLA antibodies or non-HLA DSA during the study years and we do not know whether or how often these antibodies were present. It is possible that some of the outcomes we observed, in particular the higher rates of prolonged ventilation and AMR, were related to crossing these antibodies rather than the observed pretransplant DSA. However, survival data were not different in recipients with DSA in our cohort despite the possibility of transplantation in the setting of unidentified C or DP DSA.
Conclusions
A protocol of accepting donor offers for lung transplant candidates with preformed, CDC crossmatch-negative DSA is associated with increased need for prolonged mechanical ventilation and AMR, without affecting overall or CLAD-free short-term survival.
Supplementary Material
Footnotes
Author Contributions: A.M.C., S.C., J.K., A.M., J.N., and H.J.G. contributed to the study conception, data acquisition, analysis and interpretation, drafting of the manuscript, revision of the manuscript for important intellectual content, and approval of the final copy. I.W., H.R.M., and S.E.-C. contributed to the study conception, data interpretation, revision of the manuscript for important intellectual content, and approval of the final copy.
This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org.
Author disclosures are available with the text of this article at www.atsjournals.org.
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