Plasma Donor-derived Cell-free DNA Levels Are Increased During Acute Cellular Rejection After Lung Transplant: Pilot Data

Sayah, David M.; Weigt, S. Samuel; Ramsey, Anthony R.; Ardehali, A.; Golden, Jeff; Ross, David J.

doi:10.1097/txd.0000000000001063

Cited by 33 publications

(28 citation statements)

References 13 publications

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“…Schutz et al (2019) analyzed liver transplants and observed that the diagnostic sensitivity and specificity were 90.3% and 92.9%, respectively, for graft-derived circulating DNA [30]. Sayah et al analyzed lung transplant patients and suggested that dd-cfDNAsensitivity was 73.1%, whereas its specificity was 52.9% [31]. Furthermore, in heart transplants, a diagnosis can be predicted with 92% sensitivity and 75% specificity [32].…”

Section: Discussionmentioning

confidence: 99%

Current Trends in Cell-Free DNA Applications. Scoping Review of Clinical Trials

Stawski

Stec-Martyna

Chmielecki

et al. 2021

Biology

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We aimed to summarize the current knowledge about the trends in cfDNA application based on the analysis of clinical trials registered until April 2021. International Clinical Trials Registry Platform (ICTRP) and Clinicaltrials.gov were searched with the keywords: “cf-DNA”; “Circulating DNA”; “Deoxyribonucleic Acid”; and “Cell-Free Deoxyribonucleic Acid”. Of 605 clinical trials, we excluded 237 trials, and 368 remaining ones were subject to further analysis. The subject, number of participants, and study design were analyzed. Our scoping review revealed three main trends: oncology (n = 255), non-invasive prenatal diagnostic (n = 48), and organ transplantation (n = 41), and many (n = 22) less common such as sepsis, sport, or autoimmune diseases in 368 clinical trials. Clinical trials are translating theory into clinical care. However, the diagnostic value of cfDNA remains controversial, and diagnostic accuracy still needs to be evaluated. Thus, further studies are necessary until cfDNA turns into a standard in clinical practice.

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Section: Discussionmentioning

confidence: 99%

Current Trends in Cell-Free DNA Applications. Scoping Review of Clinical Trials

Stawski

Stec-Martyna

Chmielecki

et al. 2021

Biology

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“…Dd-cfDNA levels increase during acute rejection episodes according to the severity of damage in many solid organ transplants ( 12 - 16 ). In lung transplant recipients, donor DNA levels were found to increase during acute rejection episodes ( 5 , 17 , 18 ) and during respiratory tract infections ( 5 , 19 , 20 ).…”

Section: Introductionmentioning

confidence: 99%

Validation of a Simple, Rapid, and Cost-Effective Method for Acute Rejection Monitoring in Lung Transplant Recipients

Sorbini¹,

Togliatto²,

Mioli³

et al. 2022

Transpl Int

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Despite advances in immunosuppression therapy, acute rejection remains the leading cause of graft dysfunction in lung transplant recipients. Donor-derived cell-free DNA is increasingly being considered as a valuable biomarker of acute rejection in several solid organ transplants. We present a technically improved molecular method based on digital PCR that targets the mismatch between the recipient and donor at the HLA-DRB1 locus. Blood samples collected sequentially post-transplantation from a cohort of lung recipients were used to obtain proof-of-principle for the validity of the assay, correlating results with transbronchial biopsies and lung capacity tests. The results revealed an increase in dd-cfDNA during the first 2 weeks after transplantation related to ischemia-reperfusion injury (6.36 ± 5.36%, p < 0.0001). In the absence of complications, donor DNA levels stabilized, while increasing again during acute rejection episodes (7.81 ± 12.7%, p < 0.0001). Respiratory tract infections were also involved in the release of dd-cfDNA (9.14 ± 15.59%, p = 0.0004), with a positive correlation with C-reactive protein levels. Overall, the dd-cfDNA percentages were inversely correlated with the lung function values measured by spirometry. These results confirm the value of dd-cfDNA determination during post-transplant follow-up to monitor acute rejection in lung recipients, achieved using a rapid and inexpensive approach based on the HLA mismatch between donor and recipient.

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“…Prior reports recommending a 2x-multiplier for dd-cfDNA were theoretically based on anticipated differences in total lung mass for SLT versus BLT allografts. 9 , 10 , 12 , 33 Intuitively, correction for SLT may be considered as appropriate, however, in nontransplant studies after surgical pneumonectomy the potential for lung hypertrophy and hyperplasia has been well established. 34 , 35 We found that the dd-cfDNA fraction was significantly higher (2.7-fold) in BLT than SLT in stable patients.…”

Section: Discussionmentioning

confidence: 99%

Clinical Validation of a Plasma Donor-derived Cell-free DNA Assay to Detect Allograft Rejection and Injury in Lung Transplant

Rosenheck

Ross

Botros

et al. 2022

Transplantation Direct

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Background. Lung transplant patients are vulnerable to various forms of allograft injury, whether from acute rejection (AR) (encompassing acute cellular rejection [ACR] and antibody-mediated rejection [AMR]), chronic lung allograft dysfunction (CLAD), or infection (INFXN). Previous research indicates that donor-derived cell-free DNA (dd-cfDNA) is a promising noninvasive biomarker for the detection of AR and allograft injury. Our aim was to validate a clinical plasma dd-cfDNA assay for detection of AR and other allograft injury and to confirm and expand on dd-cfDNA and allograft injury associations observed in previous studies. Methods. We measured dd-cfDNA fraction using a novel single-nucleotide polymorphism-based assay in prospectively collected plasma samples paired with clinical-pathologic diagnoses. dd-cfDNA fraction was compared across clinical-pathologic cohorts: stable, ACR, AMR, isolated lymphocytic bronchiolitis, CLAD/neutrophilic-responsive allograft dysfunction (NRAD), and INFXN. Performance characteristics were calculated for AR and combined allograft injury (AR + CLAD/NRAD + INFXN) versus the stable cohort. Results. The study included 195 samples from 103 patients. Median dd-cfDNA fraction was significantly higher for ACR (1.43%, interquartile range [IQR]: 0.67%–2.32%, P = 5 × 10 −6 ), AMR (2.50%, IQR: 2.06%–3.79%, P = 2 × 10 −5 ), INFXN (0.74%, IQR: 0.46%–1.38%, P = 0.02), and CLAD/NRAD (1.60%, IQR: 0.57%–2.60%, P = 1.4 × 10 −4 ) versus the stable cohort. Area under the receiver operator characteristic curve for AR versus stable was 0.91 (95% confidence interval [CI]: 0.83-0.98). Using a ≥1% dd-cfDNA fraction threshold, sensitivity for AR was 89.1% (95% CI: 76.2%-100.0%), specificity 82.9% (95% CI: 73.3%-92.4%), positive predictive value, 51.9% (95% CI: 37.5%-66.3%), and negative predictive value, 97.3% (95% CI: 94.3%-100%). For combined allograft injury area under the receiver operator characteristic curve was 0.76 (95% CI: 0.66-0.85), sensitivity 59.9% (95% CI: 46.0%-73.9%), specificity 83.9% (95% CI: 74.1%-93.7%), positive predictive value, 43.6% (95% CI: 27.6%-59.6%), and negative predictive value, 91.0% (95% CI: 87.9%-94.0%). Conclusions. These results indicate that our dd-cfDNA assay detects AR and other allograft injury. dd-cfDNA monitoring, accompanied by standard clinical assessments, represents a valuable precision tool to support lung transplant health and is appropriate for further assessment in a prospective randomized-controlled study.

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Plasma Donor-derived Cell-free DNA Levels Are Increased During Acute Cellular Rejection After Lung Transplant: Pilot Data

Cited by 33 publications

References 13 publications

Current Trends in Cell-Free DNA Applications. Scoping Review of Clinical Trials

Current Trends in Cell-Free DNA Applications. Scoping Review of Clinical Trials

Validation of a Simple, Rapid, and Cost-Effective Method for Acute Rejection Monitoring in Lung Transplant Recipients

Clinical Validation of a Plasma Donor-derived Cell-free DNA Assay to Detect Allograft Rejection and Injury in Lung Transplant

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