Impact of Donor Specific Antibodies on Longitudinal Lung Function and Baseline Lung Allograft Dysfunction

Muhtadi Alnababteh; Junfeng Sun; Rohan Meda; Lucia Ponor; Pali Shah; Joby Matthews; Hyesik Kong; Ananth Charya; R N Helen Luikart; Shambhu Aryal; Steven D Nathan; Jonathan B Orens; Kiran K Khush; Moon Jang; Sean Agbor-Enoh; Michael B Keller

doi:10.1016/j.healun.2025.06.012

Impact of Donor Specific Antibodies on Longitudinal Lung Function and Baseline Lung Allograft Dysfunction

J Heart Lung Transplant. 2025 Jun 26:S1053-2498(25)02038-8. doi: 10.1016/j.healun.2025.06.012. Online ahead of print.

Authors

Muhtadi Alnababteh¹, Junfeng Sun², Rohan Meda³, Lucia Ponor⁴, Pali Shah⁵, Joby Matthews⁵, Hyesik Kong⁶, Ananth Charya⁷, R N Helen Luikart⁸, Shambhu Aryal⁹, Steven D Nathan⁹, Jonathan B Orens⁵, Kiran K Khush¹⁰, Moon Jang⁶, Sean Agbor-Enoh¹¹, Michael B Keller¹²

Affiliations

¹ Laborarory of Applied Precision Omics (APO), National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health, Bethesda, MD; Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD.
² Inova Fairfax Hospital, Falls Church, VA.
³ Laboratory of Transplantation Genomics, National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health, Bethesda, MD.
⁴ Genomic Research Alliance for Transplantation (GRAfT); Division of Hospital Medicine, Johns Hopkins Bayview Medical Center, Baltimore, MD.
⁵ Genomic Research Alliance for Transplantation (GRAfT); Pulmonary and Critical Care Medicine, Johns Hopkins Hospital, Baltimore MD.
⁶ Laborarory of Applied Precision Omics (APO), National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health, Bethesda, MD; Laboratory of Transplantation Genomics, National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health, Bethesda, MD; Genomic Research Alliance for Transplantation (GRAfT).
⁷ Division of Pulmonary and Critical Care Medicine, University of Maryland Medical Center, Baltimore MD.
⁸ Genome Transplant Genomics (GTD); Division of Cardiovascular Medicine and Stanford University School of Medicine, Palo Alto, CA; Department of Pathology, Stanford University School of Medicine, Palo Alto, CA.
⁹ Genomic Research Alliance for Transplantation (GRAfT); Inova Fairfax Hospital, Falls Church, VA.
¹⁰ Genome Transplant Genomics (GTD); Division of Cardiovascular Medicine and Stanford University School of Medicine, Palo Alto, CA.
¹¹ Laborarory of Applied Precision Omics (APO), National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health, Bethesda, MD; Laboratory of Transplantation Genomics, National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health, Bethesda, MD; Genomic Research Alliance for Transplantation (GRAfT); Pulmonary and Critical Care Medicine, Johns Hopkins Hospital, Baltimore MD.
¹² Laborarory of Applied Precision Omics (APO), National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health, Bethesda, MD; Laboratory of Transplantation Genomics, National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health, Bethesda, MD; Genomic Research Alliance for Transplantation (GRAfT); Pulmonary and Critical Care Medicine, Johns Hopkins Hospital, Baltimore MD; Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD. Electronic address: mkeller1@som.umaryland.edu.

PMID: 40581272
DOI: 10.1016/j.healun.2025.06.012

Abstract

Background: Lung transplantation offers life-saving benefits for patients with end-stage lung disease, however, long-term outcomes remain poor, with a median survival of 6.5 years. Identifying patients at risk for poor post-transplant lung function is crucial for improving outcomes. While peri-operative and demographic factors have previously been studied, the impact of donor-specific antibodies (DSA) on longitudinal post-transplant lung function remains unclear. This study examines the effects of DSA on post-transplant lung function and the risk of baseline lung allograft dysfunction (BLAD).

Research question: Is DSA development linked to worse longitudinal lung function, higher BLAD rates, and poorer survival compared to DSA-negative patients regardless of the development of clinical AMR?

Methods: The study included lung transplant recipients from two prospective cohort studies, comparing DSA+ and DSA- patients. All participants underwent serial surveillance and clinically-indicated bronchoscopy, pulmonary function tests, and DSA testing. Statistical analysis included linear mixed models for longitudinal lung function data, multivariable logistic regression for BLAD, and survival analysis using Cox Proportional Hazard models.

Results: We analyzed 213 patients with a median follow-up of 48.1 months. Among them, 50.7% developed DSA. DSA+ patients showed significantly lower rates of post-transplant spirometric improvement compared to DSA- patients (p=0.008 for %FVC; p=0.02 for %FEV1). After DSA diagnosis, there was a significant decrease in the slopes of %FVC and %FEV1 (p=0.0008 and p=0.0006, respectively). DSA+ patients had a higher risk of developing BLAD (OR 2.14, 95% CI [1.45, 3.17], p=0.0001). Additionally, DSA+ patients had a higher risk of death (HR 2.98, 95% CI [1.79, 4.99], p<0.0001). These findings were consistent even when excluding patients with clinical antibody-mediated rejection (AMR).

Interpretation: Our study demonstrates that DSA development significantly impairs post-transplant lung function and increases the risk of BLAD even in the absence of clinical AMR. These findings suggest that DSA may serve as a biomarker of BLAD, and could potentially aid in risk stratification following lung transplantation.

Keywords: BLAD; DSA; Lung Transplant.