Highly Sensitive Noninvasive Cardiac Transplant Rejection Monitoring Using Targeted Quantification of Donor-Specific Cell-Free Deoxyribonucleic Acid

Hidestrand, Mats; Tomita‐Mitchell, Aoy; Hidestrand, Pip; Oliphant, Arnold; Goetsch, M.; Stamm, Karl; Liang, Huan; Castleberry, Chesney; Benson, D.Woodrow; Stendahl, Gail; Simpson, Pippa; Berger, Stuart; Tweddell, James S.; Zangwill, Steven; Mitchell, Michael E.

doi:10.1016/j.jacc.2013.09.029

Cited by 68 publications

(48 citation statements)

References 5 publications

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“…This approach is applicable to sex-matched and mismatched donor-recipients pairs. Alternative modes of cfdDNA measurement, such as methods based on targeted sequencing or PCR of specific genomic markers (16, 17), may also be a fruitful application of this approach. Targeted assays have the promise of reduced cost and can, in principle, be combined with molecular bar-coding strategies that may reduce sequencing and PCR error rates (18).…”

Section: Discussionmentioning

confidence: 99%

Circulating Cell-Free DNA Enables Noninvasive Diagnosis of Heart Transplant Rejection

et al. 2014

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Monitoring allograft health is an important component of posttransplant therapy. Endomyocardial biopsy is the current gold standard for cardiac allograft monitoring but is an expensive and invasive procedure. Proof of principle of a universal, noninvasive diagnostic method based on high-throughput screening of circulating cell-free donor-derived DNA (cfdDNA) was recently demonstrated in a small retrospective cohort. We present the results of a prospective cohort study (65 patients, 565 samples) that tested the utility of cfdDNA in measuring acute rejection after heart transplantation. Circulating cell-free DNA was purified from plasma and sequenced (mean depth, 1.2 giga–base pairs) to quantify the fraction of cfdDNA. Through a comparison with endomyocardial biopsy results, we demonstrate that cfdDNA enables diagnosis of acute rejection after heart transplantation, with an area under the receiver operating characteristic curve of 0.83 and sensitivity and specificity that are comparable to the intrinsic performance of the biopsy itself. This noninvasive genome transplant dynamics approach is a powerful and informative method for routine monitoring of allograft health without incurring the risk, discomfort, and expense of an invasive biopsy.

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Section: Discussionmentioning

confidence: 99%

Circulating Cell-Free DNA Enables Noninvasive Diagnosis of Heart Transplant Rejection

et al. 2014

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“…Characterization of effects of miscellaneous other acute medical conditions is outside the scope of the current study, which identified patients who were stable and not having acute systemic inflammatory disorders such as sepsis. The very low levels of dd-cfDNA found were quantified in relation to the large amounts of cfDNA from the recipient; this method (ratio) has been used in the majority of published studies of dd-cfDNA, and reproducibly has been associated with rejection across organ types (2)(3)(4)(5)(6)(7)(8). Although determining levels of dd-cfDNA may not eliminate the need for biopsy to aid in the confirmation of a specific histopathology, its results could increase the prebiopsy probability of detecting injury, thereby making biopsy a more effective diagnostic tool.…”

Section: Limitations Of This Studymentioning

confidence: 99%

“…Observations of increased levels of ddcfDNA during acute rejection and correlation to severity of rejection have indicated the potential utility of dd-cfDNA as an early noninvasive indicator of allograft injury (2)(3)(4)(5)(6)(7)(8). Among the various strategies to measure dd-cfDNA, we have demonstrated the analytical validity of a targeted next-generation sequencing assay that uses 266 single-nucleotide polymorphisms (SNPs) to accurately quantify dd-cfDNA in the plasma of transplant recipients without the need for genotyping either the donor or the recipient (6).…”

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confidence: 99%

Biological Variation of Donor-Derived Cell-Free DNA in Renal Transplant Recipients: Clinical Implications

Bromberg

Brennan

Poggio

et al. 2017

The Journal of Applied Laboratory Medicine

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Background Previous studies have demonstrated that donor-derived cell-free DNA (dd-cfDNA) found in circulating blood of transplant recipients may serve as a noninvasive biomarker of allograft rejection. To better interpret the clinical meaning of dd-cfDNA, it is essential to understand the biological variation of this biomarker in stable healthy recipients. This report establishes the biological variation and clinical reference intervals of dd-cfDNA in renal transplant recipients by using an analytically validated assay that has a CV of 6.8%. Methods We sampled venous blood at patient surveillance visits (typically at posttransplant months 1–4, 6, 9, and 12) in a 14-center observational study. Patients with stable renal allograft function spanning ≥3 serial visits were selected. We used AlloSure®, a targeted next-generation sequencing-based approach, to measure dd-cfDNA in the plasma and computed the intraindividual CV (CVI) and interindividual CV (CVG), the index of individuality (II), and reference change value (RCV). Results Of 93 patients, 61% were men, 56% were Caucasian, mean age was 49 years, and 63% were deceased donor kidney recipients. Of 380 blood samples, the dd-cfDNA median value was 0.21% (interquartile range 0.12%–0.39%) and the 97.5th percentile was 1.20%. In 18 patients with an average of 4.1 tests, the CVI was 21%, CVG was 37%, II was 0.57, and RCV was 61%. Conclusions In a renal transplant recipient, a dd-cfDNA level above 1.2% is out of range and potentially abnormal. A serial increase of up to 61% in level of dd-cfDNA in a patient may be attributable to biological variation. Clinicaltrials.gov Identifier: NCT02424227

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“…Several studies have provided evidence that alloreactive T cells detected in peripheral blood (21–26), the quantity of cell-free, donor DNA in recipient’s plasma (27, 28), serum angiogenesis-related factors (29–33), serum anti-HLA antibodies and autoantibodies (34–39) and several peripheral blood gene profiles are associated with acute or chronic heart graft injury (40–43). Prospective, multicenter, comparative analyses of candidate biomarkers for AR and CAV have not been reported.…”

Section: Introductionmentioning

confidence: 99%

Multicenter Analysis of Immune Biomarkers and Heart Transplant Outcomes: Results of the Clinical Trials in Organ Transplantation-05 Study

Starling

Stehlik

Baran

et al. 2016

American Journal of Transplantation

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Identification of biomarkers that assess post-transplant risk is needed to improve long-term outcomes following heart transplantation. The Clinical Trials in Organ Transplantation (CTOT)-05 protocol was an observational, multicenter, cohort study of 200 heart transplant recipients followed for the first post-transplant year. The primary endpoint was a composite of death, graft loss/re-transplantation, biopsy proven acute rejection (BPAR) and cardiac allograft vasculopathy (CAV) as defined by intravascular ultrasound (IVUS). We serially measured anti-HLA- and auto-antibodies, angiogenic proteins, peripheral blood allo-reactivity and peripheral blood gene expression patterns. We correlated assay results and clinical characteristics with the composite endpoint and its components. The composite endpoint was associated with older donor allografts (p<0.03) and with recipient anti-HLA antibody (p<0.04). Recipient CMV-negativity (regardless of donor status) was associated with BPAR p<0.001), and increases in plasma vascular endothelial growth factor-C (OR 20; 95%CI:1.9–218) combined with decreases in endothelin-1: (OR 0.14; 95%CI:0.02–0.97) associated with CAV. The remaining biomarkers showed no relationships with the study endpoints. While suboptimal endpoint definitions and lower than anticipated event rates were identified as potential study limitations, the results of this multicenter study do not yet support routine use of the selected assays as noninvasive approaches to detect BPAR and/or CAV following heart transplantation.

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Highly Sensitive Noninvasive Cardiac Transplant Rejection Monitoring Using Targeted Quantification of Donor-Specific Cell-Free Deoxyribonucleic Acid

Cited by 68 publications

References 5 publications

Circulating Cell-Free DNA Enables Noninvasive Diagnosis of Heart Transplant Rejection

Circulating Cell-Free DNA Enables Noninvasive Diagnosis of Heart Transplant Rejection

Biological Variation of Donor-Derived Cell-Free DNA in Renal Transplant Recipients: Clinical Implications

Multicenter Analysis of Immune Biomarkers and Heart Transplant Outcomes: Results of the Clinical Trials in Organ Transplantation-05 Study

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