Donor-specific antibody characteristics, including persistence and complement-binding capacity, increase risk for chronic lung allograft dysfunction

https://doi.org/10.1016/j.healun.2020.09.003Get rights and content

BACKGROUND

Chronic lung allograft dysfunction (CLAD) is the major complication limiting long-term survival in lung transplant recipients (LTRs), with those developing donor-specific anti–human leukocyte antigen (HLA) antibodies (DSAs) previously found to have increased risk for CLAD. However, as DSA responses vary in timing of development, specificity, breadth, persistence, and complement-binding capacity, we hypothesized that these characteristics would impact CLAD and survival outcomes.

METHODS

We retrospectively analyzed DSA characteristics and outcomes in a single-center cohort of 582 LTRs who had serum samples collected prospectively from 2010 to 2016. Luminex-based single antigen bead assays were performed to assess DSA.

RESULTS

DSAs were detected in 247 LTRs (42%), of which 124 (21.3%) were de novo DSAs and 53 (9.1%) were complement-binding (C1q+). CLAD developed in 208 LTRs (35.7%) during the follow-up period, with 67.8% determined as bronchiolitis obliterans syndrome phenotype and 32.2% as restrictive allograft syndrome phenotype. We found a shorter time to CLAD in LTRs with persistent DSAs (p = 0.04) and HLA-DQ–specific DSAs (p = 0.03). LTRs who developed C1q+ DSAs had significantly shorter time to CLAD (p < 0.001), with 100% of C1q+ DSAs being persistent and no differences between CLAD phenotypes. CLAD-free survival was significantly reduced in LTRs who developed C1q+ DSAs (p = 0.001), HLA-DQ–specific DSAs (p = 0.03), and multiple DSAs (p = 0.02).

CONCLUSIONS

Together, our findings demonstrate that DSA characteristics of persistence, HLA-DQ specificity, and C1q+ DSAs are associated with shorter time to CLAD. Additionally, C1q+, HLA-DQ–specific, and multiple DSAs are associated with decreased CLAD-free survival. These characteristics may improve DSA risk stratification for deleterious outcomes in LTRs.

Section snippets

Methods

This observational cohort study was approved by the University of Pittsburgh Institutional Review Board and included adult LTRs transplanted between January 1, 2010 and September 1, 2016. Patients were excluded from analysis if they did not have pulmonary function testing or post-transplant DSA testing. If a patient received multiple lung transplants during the study period, only the first transplant was included for analysis. Clinical data, including patient demographics, laboratory results,

Results

A total of 640 LTRs were initially identified as transplanted in the study timeframe. Of these, 582 met inclusion criteria and were analyzed (Figure 1). The mean age of the cohort was 55.5 years, with the majority of the LTRs being Caucasian (n = 522, 89.7%) and male (n = 333, 57.2%). The median follow-up time was 35 months (interquartile range: 16–56 months). Interstitial lung disease was the most common indication for transplant (n = 206, 35.4%). Patients were grouped according to the

Discussion

Our findings in this large, single-center study demonstrate that DSA characteristics, including persistence, DQ specificity, and complement-binding capacity as determined by the C1q-SAB assay, are independent risk factors for the development of CLAD after lung transplantation. We found that all C1q+ DSAs were persistent and that the majority (94%) exhibited specificity toward the mismatched donor HLA-DQ.

We found that, overall, 42% of LTRs had DSAs and 21% had de novo DSAs; these values are

Disclosure statement

The authors have no conflicts of interest to disclose.

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    These authors have contributed equally to this work.

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