Abstract Rationale Extreme molecular injury (EMI), defined as 5% elevations in donor-derived cell-free DNA (dd-cfDNA), has been associated with cellular stress, chronic lung allograft dysfunction (CLAD), and increased mortality in lung transplant recipients. Our prior work suggested that diabetes mellitus (DM) may be associated with increased odds of developing EMI. This study aimed to further characterize the relationship between DM, dd-cfDNA, and CLAD, while also assessing the timing of CLAD onset. Methods We conducted a retrospective analysis of 84 lung transplant recipients encompassing 729 dd-cfDNA samples. Among these, 545 samples had paired blood glucose values and 57 had hemoglobin A1c (A1c) values. dd-cfDNA levels were examined in relation to spirometry, diabetes status, and medication use, including ACE inhibitors/ARBs, metformin, and statins. Forced expiratory volume in one second (FEV1) measurements were used to identify acute lung allograft dysfunction (ALAD) and to assess chronic dysfunction based on bronchiolitis obliterans syndrome (BOS) criteria. Analyses included independent t-tests, Mann-Whitney U tests, correlation, and multivariable logistic regression. Results Diabetic recipients showed increased odds of developing EMI, though this did not reach statistical significance (p = 0.065). No significant correlations were observed between dd-cfDNA and either serum glucose or A1c. The relationship between EMI and subsequent BOS trended toward significance (p = 0.073). Recipients with EMI were significantly more likely to experience mild ALAD (aOR 5.32, p 0.001), but not moderate or severe ALAD. Among all medications evaluated, only ACE inhibitor/ARB use independently predicted EMI (aOR 2.62, p = 0.021). Finally, diabetic recipients had markedly higher odds of developing BOS (aOR 3.2, p 0.001) and a significantly shorter median time to BOS onset (190 vs. 398 days; p = 0.048) compared to non-diabetic recipients. Conclusions Diabetes in lung transplant recipients is associated with a threefold increased risk and earlier onset of BOS, with a trend toward higher EMI rates. The lack of correlation between dd-cfDNA and glycemic indices suggests that factors beyond hyperglycemia itself may contribute. One possibility is that the chronic low-grade inflammatory state characteristic of diabetes, along with heightened innate immune activation, may render the allograft more susceptible to ongoing injury, with elevated dd-cfDNA reflecting this underlying tissue damage. The observed association between ACE/ARB use and EMI may indicate vascular or endothelial stress, though this requires further study. Overall, these findings highlight the importance of investigating metabolic-immune pathways as contributors to CLAD/BOS development and progression. This abstract is funded by: None
Marquez et al. (Fri,) studied this question.