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The Use of Donor-Derived Cell-Free DNA for Assessment of Allograft Rejection and Injury Status.

ABSTRACT: Patient monitoring after kidney transplantation (KT) for early detection of allograft rejection remains key in preventing allograft loss. Serum creatinine has poor predictive value to detect ongoing active rejection as its increase is not sensitive, nor specific for acute renal allograft rejection. Diagnosis of acute rejection requires allograft biopsy and histological assessment, which can be logistically challenging in some cases and carries inherent risk for complications related to procedure. Donor-derived cell-free DNA (dd-cfDNA), DNA of donor origin in the blood of KT recipient arising from cells undergoing injury and death, has been examined as a potential surrogate marker for allograft rejection. A rise in dd-cfDNA levels precedes changes in serum creatinine allows early detections and use as a screening tool for allograft rejection. In addition, when used in conjunction with donor-specific antibodies (DSA), it increases the pre-biopsy probability of antibody-mediated rejection (ABMR) aiding the decision-making process. Advancements in noninvasive biomarker assays such as dd-cfDNA may offer the opportunity to improve and expand the spectrum of available diagnostic tools to monitor and detect risk for rejection and positively impact outcomes for KT recipients. In this this article, we discussed the evolution of dd-cfDNA assays and recent evidence of assessment of allograft rejection and injury status of KT by the use of dd-cfDNA.

SUBMITTER: Thongprayoon C

PROVIDER: S-EPMC7290747 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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The Use of Donor-Derived Cell-Free DNA for Assessment of Allograft Rejection and Injury Status.

Thongprayoon Charat C Vaitla Pradeep P Craici Iasmina M IM Leeaphorn Napat N Hansrivijit Panupong P Salim Sohail Abdul SA Bathini Tarun T Rivera Franco H Cabeza FHC Cheungpasitporn Wisit W

Journal of clinical medicine 20200514 5

Patient monitoring after kidney transplantation (KT) for early detection of allograft rejection remains key in preventing allograft loss. Serum creatinine has poor predictive value to detect ongoing active rejection as its increase is not sensitive, nor specific for acute renal allograft rejection. Diagnosis of acute rejection requires allograft biopsy and histological assessment, which can be logistically challenging in some cases and carries inherent risk for complications related to procedure ...[more]

PMID: 32423115

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Project description:BackgroundLung 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.MethodsWe 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.ResultsThe 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%).ConclusionsThese 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.

Project description:BackgroundAfter heart transplantation, endomyocardial biopsy (EMBx) is used to monitor for acute rejection (AR). Unfortunately, EMBx is invasive, and its conventional histological interpretation has limitations. This is a validation study to assess the performance of a sensitive blood biomarker-percent donor-derived cell-free DNA (%ddcfDNA)-for detection of AR in cardiac transplant recipients.MethodsThis multicenter, prospective cohort study recruited heart transplant subjects and collected plasma samples contemporaneously with EMBx for %ddcfDNA measurement by shotgun sequencing. Histopathology data were collected to define AR, its 2 phenotypes (acute cellular rejection [ACR] and antibody-mediated rejection [AMR]), and controls without rejection. The primary analysis was to compare %ddcfDNA levels (median and interquartile range [IQR]) for AR, AMR, and ACR with controls and to determine %ddcfDNA test characteristics using receiver-operator characteristics analysis.ResultsThe study included 171 subjects with median posttransplant follow-up of 17.7 months (IQR, 12.1-23.6), with 1392 EMBx, and 1834 %ddcfDNA measures available for analysis. Median %ddcfDNA levels decayed after surgery to 0.13% (IQR, 0.03%-0.21%) by 28 days. Also, %ddcfDNA increased again with AR compared with control values (0.38% [IQR, 0.31-0.83%], versus 0.03% [IQR, 0.01-0.14%]; P<0.001). The rise was detected 0.5 and 3.2 months before histopathologic diagnosis of ACR and AMR. The area under the receiver operator characteristic curve for AR was 0.92. A 0.25%ddcfDNA threshold had a negative predictive value for AR of 99% and would have safely eliminated 81% of EMBx. In addition, %ddcfDNA showed distinctive characteristics comparing AMR with ACR, including 5-fold higher levels (AMR ≥2, 1.68% [IQR, 0.49-2.79%] versus ACR grade ≥2R, 0.34% [IQR, 0.28-0.72%]), higher area under the receiver operator characteristic curve (0.95 versus 0.85), higher guanosine-cytosine content, and higher percentage of short ddcfDNA fragments.ConclusionsWe found that %ddcfDNA detected AR with a high area under the receiver operator characteristic curve and negative predictive value. Monitoring with ddcfDNA demonstrated excellent performance characteristics for both ACR and AMR and led to earlier detection than the EMBx-based monitoring. This study supports the use of %ddcfDNA to monitor for AR in patients with heart transplant and paves the way for a clinical utility study. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02423070.

Dataset Information

The Use of Donor-Derived Cell-Free DNA for Assessment of Allograft Rejection and Injury Status.

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The Use of Donor-Derived Cell-Free DNA for Assessment of Allograft Rejection and Injury Status.

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