Assessment of dd-cfDNA Levels in Clinically Stable Lung Allograft Recipients Beyond the Initial 2 y Posttransplant

Abstract

The authors had full oversight over study design, data collection and analysis, and article preparation. Lung TransplantationBackground. Donor-derived cell-free DNA (dd-cfDNA) is a useful biomarker for the diagnosis of acute allograft injury within the first 1 to 2 y after lung transplant, but its utility for diagnosing chronic lung allograft dysfunction (CLAD) has not yet been studied. Understanding baseline dd-cfDNA kinetics beyond the initial 2 y posttransplant is a necessary first step in determining the utility of dd-cfDNA as a CLAD biomarker. We seek to establish baseline dd-cfDNA% levels in clinically stable lung allograft recipients who are >2 y posttransplant. Methods. We performed a prospective, single-center, observational study to identify plasma dd-cfDNA levels in clinically stable lung allograft recipients >2 y posttransplant. Results. Fiftyone subjects were enrolled and ≥3 baseline dd-cfDNA measurements were acquired during a median of 252 d. The median baseline percent dd-cfDNA level in our cohort was 0.45% (interquartile range [IQR], 0.26-0.69). There were statistically significant differences in dd-cfDNA based on posttransplant duration (≤5 y posttransplant median 0.41% [IQR, 0.21-0.64] versus >5 y posttransplant median 0.50% [IQR, 0.33-0.76]; P < 0.02). However, the clinical significance of this small change in dd-cfDNA is uncertain because this magnitude of change is within the biologic test variation of 73%. Conclusions. This study is the first to define levels of dd-cfDNA in clinically stable patients who are >2 y post-lung transplant. These findings lay the groundwork for the study of dd-cfDNA as a possible biomarker for CLAD.

Relative Change in Donor-Derived Cell-free DNA is Superior to Absolute Values for Diagnosis of Acute Lung Allograft Dysfunction

“…3-6 Recently, our group defined baseline dd-cfDNA% levels in a prospective, noninterventional cohort of 51 lung allograft recipients who did not have acute or chronic allograft dysfunction ≥2 y posttransplant. 7 The median dd-cfDNA% in this stable cohort was 0.45 (interquartile range, 0.26–0.69), intraindividual variation (CV I ) was 26%, and interindividual variation (CV G ) was 47%, resulting in a reference change value (RCV) of 73%. This work is an important foundational step toward the potential use dd-cfDNA% as a biomarker for detection of chronic lung allograft dysfunction (CLAD).…”

“…Patient demographics, inclusion criteria, and exclusion criteria were previously reported. 7 Briefly, adult single or bilateral lung allograft recipients with stable lung function were included in the analysis if there were ≥2 baseline dd-cfDNA% measurements, each >1 mo apart. Immunosuppression and other management details have previously been reported.…”

“…We then categorized whether relative change exceeded the previously established RCV of 73% or whether absolute dd-cfDNA% at the time of ALAD exceeded a threshold of 1%. 7 To assess test characteristics in patients without ALAD, the greatest routinely measured dd-cfDNA% value available was referenced to the average baseline value.…”

Lung Transplantation for Pulmonary Artery Hypertension

“…Clearly, the outcome following LT has improved due to technological advances in all fields, leading to a better understanding of immunology, translating into better care postoperatively-in terms of diagnosis and treatment of rejection. While donorderived cell-free deoxyribonucleic acid (dd-cfDNA) has been available [106,107], methods using donor-derived cell-free ribonucleic acid (dd-cfRNA) as a liquid biopsy to give us early warning signs prior to the development of clinical rejection is very promising. Developments and advancements in the equipment for MCS further improve outcomes.…”

A Hospitable Home? Cell-Free DNA and the Inflammatory Milieu in Lung Transplant Candidates

“…Only recently has cfDNA been used as a “liquid biopsy” for rejection in solid organ transplantation ( 8 ). Donor-derived cfDNA has emerged as a specific marker of acute allograft dysfunction in lung transplant recipients, with a high negative predictive value for acute cellular rejection and antibody-mediated rejection ( 9 , 10 ). In fact, during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, a clinical protocol that relied heavily on donor-derived cfDNA to noninvasively assess allograft health was shown to reduce the need for surveillance bronchoscopies by >80% ( 11 ).…”