Abstract:Histologic analysis of the allograft biopsy specimen is the standard method used to differentiate rejection from other injury in kidney transplants. Donor-derived cell-free DNA (dd-cfDNA) is a noninvasive test of allograft injury that may enable more frequent, quantitative, and safer assessment of allograft rejection and injury status. To investigate this possibility, we prospectively collected blood specimens at scheduled intervals and at the time of clinically indicated biopsies. In 102 kidney recipients, we… Show more
“…11 Differences in baseline dd-cfDNA levels may reflect differences in the rate of cell turnover within the allograft. This is in contrast to stable kidney transplant recipients, in whom dd-cfDNA is detected at a median of 0.21% by using the AlloSure ® assay.…”
Standardized donor‐derived cell‐free DNA (dd‐cfDNA) testing has been introduced into clinical use to monitor kidney transplant recipients for rejection. This report describes the performance of this dd‐cfDNA assay to detect allograft rejection in samples from heart transplant (HT) recipients undergoing surveillance monitoring across the United States. Venous blood was longitudinally sampled from 740 HT recipients from 26 centers and in a single‐center cohort of 33 patients at high risk for antibody‐mediated rejection (AMR). Plasma dd‐cfDNA was quantified by using targeted amplification and sequencing of a single nucleotide polymorphism panel. The dd‐cfDNA levels were correlated to paired events of biopsy‐based diagnosis of rejection. The median dd‐cfDNA was 0.07% in reference HT recipients (2164 samples) and 0.17% in samples classified as acute rejection (35 samples; P = .005). At a 0.2% threshold, dd‐cfDNA had a 44% sensitivity to detect rejection and a 97% negative predictive value. In the cohort at risk for AMR (11 samples), dd‐cfDNA levels were elevated 3‐fold in AMR compared with patients without AMR (99 samples, P = .004). The standardized dd‐cfDNA test identified acute rejection in samples from a broad population of HT recipients. The reported test performance characteristics will guide the next stage of clinical utility studies of the dd‐cfDNA assay.
“…11 Differences in baseline dd-cfDNA levels may reflect differences in the rate of cell turnover within the allograft. This is in contrast to stable kidney transplant recipients, in whom dd-cfDNA is detected at a median of 0.21% by using the AlloSure ® assay.…”
Standardized donor‐derived cell‐free DNA (dd‐cfDNA) testing has been introduced into clinical use to monitor kidney transplant recipients for rejection. This report describes the performance of this dd‐cfDNA assay to detect allograft rejection in samples from heart transplant (HT) recipients undergoing surveillance monitoring across the United States. Venous blood was longitudinally sampled from 740 HT recipients from 26 centers and in a single‐center cohort of 33 patients at high risk for antibody‐mediated rejection (AMR). Plasma dd‐cfDNA was quantified by using targeted amplification and sequencing of a single nucleotide polymorphism panel. The dd‐cfDNA levels were correlated to paired events of biopsy‐based diagnosis of rejection. The median dd‐cfDNA was 0.07% in reference HT recipients (2164 samples) and 0.17% in samples classified as acute rejection (35 samples; P = .005). At a 0.2% threshold, dd‐cfDNA had a 44% sensitivity to detect rejection and a 97% negative predictive value. In the cohort at risk for AMR (11 samples), dd‐cfDNA levels were elevated 3‐fold in AMR compared with patients without AMR (99 samples, P = .004). The standardized dd‐cfDNA test identified acute rejection in samples from a broad population of HT recipients. The reported test performance characteristics will guide the next stage of clinical utility studies of the dd‐cfDNA assay.
“…1 Total cfDNA levels may rise in a variety of physiologic and pathologic states. [4][5][6] To date, there has been one large published prospective clinical study evaluating the diagnostic validity of plasma gd-cfDNA for allograft dysfunction in kidney transplantation. 2,3 Higher levels of total cfDNA have been associated with increased severity or poorer prognosis in some of these diseases.…”
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confidence: 99%
“…These include exercise, malignancy, sepsis, myocardial infarction, stroke, and critical illness. 6 A possible limitation of the method raised by this group is the potential for confounding of graft fraction by concurrent elevations in total cfDNA, an issue also observed in noninvasive prenatal testing. 2,3 In transplantation, it has been proposed that injury to the allograft results in increased release of gd-cfDNA into recipient plasma via graft-cell apoptosis and necrosis.…”
Graft‐derived cell‐free DNA (donor‐derived cell‐free DNA) is an emerging marker of kidney allograft injury. Studies examining the clinical validity of this biomarker have previously used the graft fraction, or proportion of total cell‐free DNA that is graft‐derived. The present study evaluated the diagnostic validity of absolute measurements of graft‐derived cell‐free DNA, as well as calculated graft fraction, for the diagnosis of graft dysfunction. Plasma graft‐derived cell‐free DNA, total cell‐free DNA, and graft fraction were correlated with biopsy diagnosis as well as individual Banff scores. Sixty‐one samples were included in the analysis. For the diagnosis of antibody mediated rejection, the receiver‐operator characteristic area under the curves of graft‐derived cell‐free DNA and graft fraction were 0.91 (95% CI 0.82‐0.98) and 0.89 (95% CI 0.79‐0.98), respectively. Both measures did not diagnose borderline or type 1A cellular mediated rejection. Graft fraction was associated with a broader range of Banff lesions, including lesions associated with cellular mediated rejection, while graft‐derived cell‐free DNA appeared more specific for antibody mediated rejection. Limitations of this study include a small sample size and lack of a validation cohort. The capacity for absolute quantification, and lower barriers to implementation of this methodology recommend it for further study.
“…In this study, we evaluated the dd-cfDNA in patients with more than one kidney transplant. 4 We also examined dd-cfDNA levels in all 11 RKTR patients (9 In RKTRs, at the time of clinically indicated biopsies, dd-cfDNA is significantly higher in patients with biopsy-proven rejection than in patients without rejection. These cohorts were drawn from the Circulating Donor-Derived Cell-Free DNA in Blood for Diagnosing Acute Rejection in Kidney Transplant Recipients (DART) study (ClinicalTrials.gov Identifier: NCT02424227), 4 where surveillance for rejection began less than 2 months posttransplant and there was no clinically indicated biopsy at the first visit and no rejection while on the study.…”
Section: Repeat Kidney Transplant Recipients With Active Rejection Hamentioning
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