The impact of pre-transplant allosensitization on outcomes after lung transplantation

doi:10.1016/j.healun.2015.06.003

The Journal of Heart and Lung Transplantation

Volume 34, Issue 11, November 2015, Pages 1415-1422

https://doi.org/10.1016/j.healun.2015.06.003 Get rights and content

Background

Allosensitization can be a significant barrier to transplantation for some patients, and previous studies suggested that pre-transplant allosensitization was associated with worse outcomes after lung transplantation. However, human leukocyte antigen (HLA) antibody testing has evolved significantly over the past 10 years, and current assays are highly sensitive and specific.

Methods

We examined the impact of pre-transplant allosensitization on post-transplant outcomes in the era of solid-phase multiplex HLA antibody detection assays in this retrospective, single-center study of 304 adult transplant recipients between January 1, 2006, and December 31, 2012. We accepted donor organs for allosensitized patients if a virtual crossmatch was compatible with all previously identified antibodies.

Results

In univariate and multivariate Cox proportional hazards models, pre-transplant allosensitization, the calculated panel reactive antibody, and the number of pre-transplant HLA antibodies were not associated with the development of acute cellular rejection, lymphocytic bronchiolitis, donor-specific HLA antibodies, chronic lung allograft dysfunction, or graft failure.

Conclusions

Pre-transplant allosensitization does not adversely affect outcomes after lung transplantation when the potentially reactive HLAs are avoided in the donor by a virtual crossmatch with the recipient.

Section snippets

Study design

We conducted a retrospective cohort study including all patients listed for lung transplantation at our program between January 1, 2006, and December 31, 2011. During this period, 368 patients were listed for transplantation; 3 subsequently underwent transplant at another institution and were excluded. Of the remaining 365 patients, 304 underwent transplant at our center before December 31, 2012, and comprise this cohort. The remaining 61 patients died while on the waitlist, were removed from

Baseline characteristics and histocompatibility

Follow-up was complete through December 31, 2013, and the study included 974 patient-years of follow-up with a mean follow-up of 3.2 ± 1.9 years. Among the 304 recipients, 108 (35.5%) were allosensitized before transplantation, and 196 (64.5%) were not allosensitized (Table 1). Overall, there was no significant difference in baseline characteristics between recipients who were allosensitized and recipients who were not allosensitized (Table 1). Among the 108 allosensitized recipients, 29 (27%)

Discussion

In this study, we examined the impact of pre-transplant allosensitization on post-transplant outcomes in the era of solid-phase multiplex HLA antibody detection assays and virtual crossmatching. Our analysis did not reveal any association between pre-transplant allosensitization and adverse outcomes after lung transplantation. Specifically, we found no association between pre-transplant allosensitization and the development of ACR, LB, DSA, CLAD, or graft failure. Moreover, we found no

Disclosure statement

This work was supported in part the National Institutes of Health (Grant No. HL056643 to T.M. and R.R.H. and Grant No. HL105412 to R.D.Y., T.M., and R.R.H.).

None of the authors has a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose.

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Lung transplantation despite preformed donor-specific antihuman leukocyte antigen antibodies: a 9-year single-center experience
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Pretransplant allosensitization to human leukocyte antigens (HLA) increases the recipient’s waiting list time and mortality in lung transplantation. Rather than waiting for crossmatch-negative donors, since 2013, recipients with preformed donor-specific antiHLA antibodies (pfDSA) have been managed with repeated IgA- and IgM-enriched intravenous immunoglobulin (IgGAM) infusions, usually in combination with plasmapheresis before IgGAM and a single dose of antiCD20 antibody. This retrospective study presents our 9-year experience with patients transplanted with pfDSA. Records of patients transplanted between February 2013 and May 2022 were reviewed. Outcomes were compared between patients with pfDSA and those without any de novo donor-specific antiHLA antibodies. The median follow-up time was 50 months. Of the 1,043 patients who had undergone lung transplantation, 758 (72.7%) did not develop any early donor-specific antiHLA antibodies, and 62 (5.9%) patients exhibited pfDSA. Among the 52 (84%) patients who completed treatment, pfDSA was cleared in 38 (73%). In pfDSA vs control patients and at 8-year follow-up, respectively, graft survival (%) was 75 vs 65 (P = .493) and freedom from chronic lung allograft dysfunction (%) was 63 vs 65 (P = .525). In lung transplantation, crossing the preformed HLA-antibody barrier is safe using a treatment protocol based on IgGAM. Patients with pfDSA have a good 8-year graft survival rate and freedom from chronic lung allograft dysfunction, similar to control patients.
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The allograft injury marker CXCL9 determines prognosis of anti-HLA antibodies after lung transplantation
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Despite the common detection of non-donor specific anti-HLA antibodies (non-DSAs) after lung transplantation, their clinical significance remains unclear. In this retrospective single-center cohort study of 325 lung transplant recipients, we evaluated the association between donor-specific HLA antibodies (DSAs) and non-DSAs with subsequent CLAD development. DSAs were detected in 30% of recipients and were associated with increased CLAD risk, with higher HRs for both de novo and high MFI (>5000) DSAs. Non-DSAs were detected in 56% of recipients, and 85% of DSA positive tests had concurrent non-DSAs. In general, non-DSAs did not increase CLAD risk in multivariable models accounting for DSAs. However, non-DSAs in conjunction with high BAL CXCL9 levels were associated with increased CLAD risk. Multivariable proportional hazards models demonstrate the importance of the HLA antibody-CXCL9 interaction: CLAD risk increases when HLA antibodies (both DSAs and non-DSAs) are detected in conjunction with high CXCL9. Conversely, CLAD risk is not increased when HLA antibodies are detected with low CXCL9. This study supports the potential utility of BAL CXCL9 measurement as a biomarker to risk stratify HLA antibodies for future CLAD. The ability to discriminate between high versus low-risk HLA antibodies may improve management by allowing for guided treatment decisions.
Consensus document for the selection of lung transplant candidates: An update from the International Society for Heart and Lung Transplantation
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Citation Excerpt :
Human Leucocyte Antigen (HLA) Antibodies: Elevated HLA specific antibodies detected in peripheral blood may make finding a compatible donor difficult and may predict poor outcomes.59-61 However, some centers describe successful lung transplantation despite positive cross match.62,63 Cut-off levels for organ acceptance and the optimal methods for detection of functional donor specific antibodies have not been determined.
Tens of thousands of patients with advanced lung diseases may be eligible to be considered as potential candidates for lung transplant around the world each year. The timing of referral, evaluation, determination of candidacy, and listing of candidates continues to pose challenges and even ethical dilemmas. To address these challenges, the International Society for Heart and Lung Transplantation appointed an international group of members to review the literature, to consider recent advances in the management of advanced lung diseases, and to update prior consensus documents on the selection of lung transplant candidates. The purpose of this updated consensus document is to assist providers throughout the world who are caring for patients with pulmonary disease to identify potential candidates for lung transplant, to optimize the timing of the referral of these patients to lung transplant centers, and to provide transplant centers with a framework for evaluating and selecting candidates. In addition to addressing general considerations and providing disease specific recommendations for referral and listing, this updated consensus document includes an ethical framework, a recognition of the variability in acceptance of risk between transplant centers, and establishes a system to account for how a combination of risk factors may be taken into consideration in candidate selection for lung transplantation.
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Chronic Obstructive Pulmonary Disease is the leading cause of death amongst chronic respiratory diseases. Because of its protracted course, COPD is the most important contributor to the number of years lived with disability. Over the last 40 years lung transplantation has emerged as the predominant surgical treatment for patients with end stage respiratory diseases. The interplay of variable lung function decline, comorbidities and overlap with other respiratory diseases hinder easy selection of COPD candidates for transplantation. Post-transplantation, perioperative mortality continues to decrease but chronic allograft dysfunction, infections and complications of immunossupresive regimens continue to be major barriers to long term survival.

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Original Clinical ScienceThe impact of pre-transplant allosensitization on outcomes after lung transplantation

Background

Methods

Results

Conclusions

Section snippets

Study design

Baseline characteristics and histocompatibility

Discussion

Disclosure statement

The Registry of the International Society for Heart and Lung Transplantation: thirty-first adult lung and heart-lung transplant report—2014; focus theme: retransplatnation

J Heart Lung Transplant

HLA-A locus mismatches and development of antibodies to HLA after lung transplantation correlate with the development of bronchiolitis obliterans syndrome

Transplantation

Development of ELISA-detected anti-HLA antibodies precedes the development of bronchiolitis obliterans syndrome and correlates with progressive decline in pulmonary function after lung transplantation

Transplantation

Development of an antibody specific to major histocompatibility antigens detectable by flow cytometry after lung transplant is associated with bronchiolitis obliterans syndrome

Transplantation

De novo donor HLA-specific antibodies predict development of bronchiolitis obliterans syndrome after lung transplantation

J Heart Lung Transplant

De novo donor-specific HLA antibodies are associated with early and high-grade bronchiolitis obliterans syndrome and death after lung transplantation

J Heart Lung Transplant

HLA-specific antibodies are risk factors for lymphocytic bronchiolitis and chronic lung allograft dysfunction

Am J Transplant

HLA-specific antibodies are associated with high-grade and persistent-recurrent lung allograft acute rejection

J Heart Lung Transplant

Acute antibody-mediated rejection after lung transplantation

J Heart Lung Transplant

Implications for human leukocyte antigen antibodies after lung transplantation: a 10-year experience in 441 patients

Chest

Influence of panel-reactive antibody on survival and rejection after lung transplantation

J Heart Lung Transplant

Influence of panel-reactive antibodies on posttransplant outcomes in lung transplant recipients

Ann Thorac Surg

Original Clinical Science
The impact of pre-transplant allosensitization on outcomes after lung transplantation