Solid Gold, or Liquid Gold?
2021; Lippincott Williams & Wilkins; Volume: 143; Issue: 12 Linguagem: Inglês
10.1161/circulationaha.120.052925
ISSN1524-4539
Autores Tópico(s)Renal Transplantation Outcomes and Treatments
ResumoHomeCirculationVol. 143, No. 12Solid Gold, or Liquid Gold? Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBSolid Gold, or Liquid Gold?Towards a New Diagnostic Standard for Heart Transplant Rejection Michelle M. Kittleson, MD, PhD and Sonia Garg, MD Michelle M. KittlesonMichelle M. Kittleson Michelle M. Kittleson, MD, PhD, 8536 Wilshire Blvd, Suite 301, Los Angeles, CA 90211. Email E-mail Address: [email protected] https://orcid.org/0000-0003-4492-2691 Department of Cardiology, Smidt Heart Institute, Cedars-Sinai, Los Angeles, CA (M.M.K.). and Sonia GargSonia Garg Division of Cardiology, University of Texas Southwestern Medical Center, Dallas (S.G.). Originally published22 Mar 2021https://doi.org/10.1161/CIRCULATIONAHA.120.052925Circulation. 2021;143:1198–1201This article is a commentary on the followingCell-Free DNA to Detect Heart Allograft Acute Rejectionis corrected byCorrection to: Solid Gold, or Liquid Gold?: Towards a New Diagnostic Standard for Heart Transplant RejectionOther version(s) of this articleYou are viewing the most recent version of this article. Previous versions: March 22, 2021: Previous Version of Record Article, see p 1184The endomyocardial biopsy has been the gold standard for diagnosis of heart transplant rejection since first pioneered by surgeon Dr Phillip Caves and pathologist Dr Margaret Billingham at Stanford in the early 1970s. A decade earlier, in Japan, a percutaneous method of obtaining cardiac tissue had been reported1 but never used in heart transplant recipients. Dr Caves obtained a bioptome from Japan and improved the design using a canine model of heart transplantation.2 Dr Billingham prepared the endomyocardial biopsy (EMB) samples and cataloged the pathological findings, and the field of heart transplant pathology was born.3Since then, sensitive noninvasive diagnostic tools for early detection of transplant injury have remained an unmet need in heart transplantation. Many noninvasive methods have been evaluated, including parameters from electrocardiography, echocardiography, cardiac magnetic resonance imaging, and positron emission tomography, as well as biomarkers such as troponin and B-type natriuretic peptide; however, all these methods offer limited sensitivity and specificity. Noninvasive peripheral gene expression testing is the most promising noninvasive alternative to the EMB, with a 99% negative predictive value for acute cellular rejection (ACR; AlloMap, CareDx, Inc).4 However, peripheral gene expression testing offers limited positive predictive value for ACR and was not designed to detect antibody-mediated rejection (AMR), a major barrier as the treatment, surveillance, and prognosis of AMR differ greatly from ACR.5Donor-derived cell-free DNA (ddcfDNA) is a new noninvasive approach to detect rejection that may improve on peripheral gene expression testing. The discovery of cell-free DNA dates back to 1948, when it was identified in the sera of patients with cancer.6 The significance of this observation went unrecognized for decades, although with advances in genetic sequencing cell-free DNA is now a biomarker for prenatal testing and cancer. In organ transplantation, ddcfDNA was proposed as a noninvasive indicator of graft injury on the basis of the hypothesis that acute rejection causes cell death in the allograft, which leads to increased levels of ddcfDNA in the blood of transplant recipients.7 However, early technologies to quantify ddcfDNA in transplant patients were costly and often impractical, requiring either sex mismatch between donor and recipient (to use the Y chromosome to distinguish donor from recipient DNA)8 or previous genotyping of the donor and recipient.9These barriers were overcome with the development of a targeted amplification, next-generation sequencing assay relying on single nucleotide polymorphisms.10 For the ddcfDNA assay to be applicable to different transplant recipients without requiring separate genotyping of either donor or recipient, specific single nucleotide polymorphisms were selected because they could differentiate between any 2 unrelated individuals. Thus, the percentage of ddcfDNA in transplant recipients' blood could be determined without the need for donor or recipient genotyping.Currently, one ddcfDNA assay (AlloSure, CareDx, Inc) is available for clinical use through the Surveillance HeartCare Outcomes Registry (NCT03695601). This assay was assessed in a previous transplant registry (Donor-Derived Cell-Free DNA-Outcomes AlloMap Registry), and the level of ddcfDNA was significantly higher in patients with ACR or AMR than in those with no evidence of rejection on EMB.11 At a cutoff of 0.2%, the ddcfDNA assay had 80% specificity and 44% sensitivity to differentiate acute rejection from no rejection, earning ddcfDNA the moniker of "the liquid biopsy." However, the Donor-Derived Cell-Free DNA-Outcomes AlloMap Registry included a change in protocol midway through patient recruitment whereby ddcfDNA specimens were obtained only when patients had a clinical suspicion of rejection and a planned "for cause" biopsy to increase the number of rejection events; thus, the test characteristics could not be fully evaluated.In this issue of Circulation, Agbor-Enoh et al12 report the performance characteristics of another ddcfDNA assay to detect heart transplant rejection and address some of the knowledge gaps from previous analyses. This multicenter study GRAfT (Genomic Research Alliance for Transplantation), sponsored by the National Heart, Lung, and Blood Institute, was composed of 171 heart transplant recipients from 5 centers. The study's ddcfDNA assay involved similar techniques to the AlloSure assay but with a significant difference: Pretransplant donor and recipient genotyping was required. The findings confirmed those of previous studies: ddcfDNA levels were higher in samples classified as acute rejection,7,9,10,11 were able to detect AMR as well as ACR,11 and were higher in patients with evidence of graft dysfunction.11However, the current study offers novel insights with tantalizing implications. Not only could the ddcfDNA assay accurately detect AMR in addition to cellular rejection, but the 2 forms of rejection differed in the pattern of ddcfDNA elevation as well as fragment length and genomic composition of ddcfDNA. The ddcfDNA levels were higher with AMR versus ACR overall and also were relatively higher at each histopathologic grade. In addition, the rise in ddcfDNA occurred before histopathologic evidence of rejection in AMR but not ACR. In 80% of cases of AMR, the rise in ddcfDNA was detected 3.2 months before diagnostic changes on EMB, whereas in ACR, the rise in ddcfDNA was coincident with changes on EMB in ?90% of cases. These observations provide evidence of the first noninvasive assay with the ability to distinguish between these 2 forms of rejection: a true "liquid biopsy."In this study, a ddcfDNA threshold of 0.25% had an area under the curve of 0.92 for acute rejection with a negative predictive value of 99% and a sensitivity of 81%.12 What are the clinical implications of these test characteristics? A sensitivity of 81% means that 81% of all rejection episodes were detected by the ddcfDNA assay, and thus 81% of routine endomyocardial biopsies could have been avoided, amounting to 751 of the 923 routine biopsies in this study. Furthermore, the negative predictive value of 99% translated to 6 episodes of missed rejection by the ddcfDNA assay, although only 1 was associated with a fall in ejection fraction. Whether this balance, saving 751 biopsies at the cost of 6 episodes of rejection (5 asymptomatic), is acceptable will be at each clinician's discretion, but the risk of morbidity, discomfort, and resource use with EMB13 must also be factored into the equation.The positive predictive value of the ddcfDNA assay of 19.6% also bears examination. In 135 cases, the ddcfDNA assay was elevated >0.25%, but concurrent EMB showed no histopathologic rejection. Were all these 135 cases false positives? Probably not: 20.7% occurred in the setting of allograft dysfunction and, even more interesting, 44.1% preceded histopathologic evidence of rejection or graft dysfunction. These findings suggest that the stalwart EMB may not be the true gold standard for the diagnosis of rejection but rather an indicator that comes too late.This study offers the potential rationale for ddcfDNA to someday be incorporated into the routine rejection surveillance algorithm for heart transplant recipients (Figure). However, as with any good study, these findings raise as many questions as they answer. The authors used a ddcfDNA assay, which required donor genotyping. Will these results, especially the ability to distinguish AMR from ACR, also be observed with the ddcfDNA assay that is currently clinically available (AlloSure) and does not require donor genotyping? In the diagnostic algorithm for rejection, what will be the complementary roles and indications for a gene expression profiling assay, the ddcfDNA assay, and the EMB? In patients for whom the ddcfDNA levels are consistent with AMR but the EMB shows no changes, will there be benefit from early treatment guided by ddcfDNA, and can ddcfDNA levels be followed as an indicator of response to rejection therapy? Will elevated ddcfDNA be useful later after transplant to assess for graft injury related to subclinical or microvascular cardiac allograft vasculopathy?Download figureDownload PowerPointFigure. A proposed clinical algorithm for the use of ddcfDNA in clinical practice. Heart transplant recipients >30 days from transplant (when ddcfDNA levels stabilize) undergo clinical evaluation for symptoms and signs of rejection. Stable patients not at center-specific milestones (typically 3, 6, and 12 months after transplant) may be screened with echocardiogram, gene expression profiling, and ddcfDNA. If ddcfDNA, gene expression assay, or echocardiogram is abnormal, or if the patient has symptoms or signs consistent with rejection, endomyocardial biopsy and assessment of anti-HLA antibodies would be indicated. If abnormal findings are present, antirejection therapy would commence on the basis of the patient's specific findings and clinical severity. If endomyocardial biopsy and anti-HLA antibodies disclose no abnormalities in the context of elevated ddcfDNA levels, then the patient would undergo more frequent surveillance than routine and may undergo angiogram to exclude cardiac allograft vasculopathy. Unanswered questions about the role of ddcfDNA in the management of heart transplant recipients are shown in the blue italicized text. ACR 2R indicates acute cellular rejection grade 2R; AMR1, antibody-mediated rejection grade 1; CAV; cardiac allograft vasculopathy; ddcfDNA, donor-derived cell-free DNA; EF, ejection fraction; EMB, endomyocardial biopsy; and HLA, human leukocyte antigen.Whether this liquid biopsy ousts the EMB as the gold standard for the diagnosis of heart transplant rejection remains to be seen. We await with anticipation future investigations to address these unanswered questions about ddcfDNA and a time when such a noninvasive assay, rather than invasive EMB, becomes the gold standard of rejection surveillance for heart transplant recipients.Disclosures None.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.https://www.ahajournals.org/journal/circMichelle M. Kittleson, MD, PhD, 8536 Wilshire Blvd, Suite 301, Los Angeles, CA 90211. Email michelle.[email protected]orgReferences1. Sakakibara S, Konno S. Endomyocardial biopsy.Jpn Heart J. 1962; 3:537–543. doi: 10.1536/ihj.3.537CrossrefMedlineGoogle Scholar2. Reitz BA. 50th anniversary landmark commentary on Caves PK, Stinson EB, Billingham M, Shumway NE. Percutaneous transvenous endomyocardial biopsy in human heart recipients: experience with a new technique. Ann Thorac Surg 1973;16:325-36.Ann Thorac Surg. 2015; 99:1875–6. doi: 10.1016/j.athoracsur.2015.04.071CrossrefMedlineGoogle Scholar3. Caves PK, Stinson EB, Billingham M, Shumway NE. Percutaneous transvenous endomyocardial biopsy in human heart recipients: experience with a new technique.Ann Thorac Surg. 1973; 16:325–336. doi: 10.1016/s0003-4975(10)65002-3CrossrefMedlineGoogle Scholar4. Deng MC, Eisen HJ, Mehra MR, Billingham M, Marboe CC, Berry G, Kobashigawa J, Johnson FL, Starling RC, Murali S, et al.; CARGO Investigators. Noninvasive discrimination of rejection in cardiac allograft recipients using gene expression profiling.Am J Transplant. 2006; 6:150–160. doi: 10.1111/j.1600-6143.2005.01175.xCrossrefMedlineGoogle Scholar5. 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Noninvasive detection of graft injury after heart transplant using donor-derived cell-free DNA: a prospective multicenter study.Am J Transplant. 2019; 19:2889–2899. doi: 10.1111/ajt.15339CrossrefMedlineGoogle Scholar12. Agbor-Enoh S, Shah P, Tunc I, Hsu S, Russell S, Feller E, Shah K, Rodrigo ME, Najjar SS, Kong H, et al.. Cell-free DNA to detect heart allograft acute rejection.Circulation. 2021; 143:1184–1197. doi: 10.1161/CIRCULATIONAHA.120.049098LinkGoogle Scholar13. Baraldi-Junkins C, Levin HR, Kasper EK, Rayburn BK, Herskowitz A, Baughman KL. Complications of endomyocardial biopsy in heart transplant patients.J Heart Lung Transplant. 1993; 121 pt 163–67.MedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Feingold B, Rose‐Felker K, West S, Zinn M, Berman P, Moninger A, Huston A, Stinner B, Xu Q, Zeevi A and Miller S (2021) Early findings after integration of donor‐derived cell‐free DNA into clinical care following pediatric heart transplantation, Pediatric Transplantation, 10.1111/petr.14124, 26:1, Online publication date: 1-Feb-2022. Kim P, Olymbios M, Siu A, Wever Pinzon O, Adler E, Liang N, Swenerton R, Sternberg J, Kaur N, Ahmed E, Chen Y, Fehringer G, Demko Z, Billings P and Stehlik J (2022) A novel donor-derived cell-free DNA assay for the detection of acute rejection in heart transplantation, The Journal of Heart and Lung Transplantation, 10.1016/j.healun.2022.04.002, 41:7, (919-927), Online publication date: 1-Jul-2022. Liu Z, Perry L, Penny-Dimri J, Handscombe M, Overmars I, Plummer M, Segal R and Smith J (2022) Elevated Cardiac Troponin to Detect Acute Cellular Rejection After Cardiac Transplantation: A Systematic Review and Meta-Analysis, Transplant International, 10.3389/ti.2022.10362, 35 Related articlesCell-Free DNA to Detect Heart Allograft Acute RejectionSean Agbor-Enoh, et al. Circulation. 2021;143:1184-1197Correction to: Solid Gold, or Liquid Gold?: Towards a New Diagnostic Standard for Heart Transplant RejectionCirculation. 2021;143:e1029-e1029 March 23, 2021Vol 143, Issue 12 Advertisement Article InformationMetrics © 2021 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.120.052925PMID: 33750203 Originally publishedMarch 22, 2021 Keywordsrejectionheart transplantendomyocardial biopsycell-free DNAEditorialsPDF download Advertisement SubjectsCardiomyopathyHeart Failure
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