Donor-derived cell-free DNA levels predict graft injury in liver transplant recipients

Josh Levitsky, Manoj Kandpal, Kexin Guo, Steve Kleiboeker, Rohita Sinha, Michael Abecassis, Josh Levitsky, Manoj Kandpal, Kexin Guo, Steve Kleiboeker, Rohita Sinha, Michael Abecassis

Abstract

Donor-derived cell-free DNA (dd-cfDNA) has been evaluated as a rejection marker in organ transplantation. This study sought to assess the utility of dd-cfDNA to diagnose graft injury in liver transplant recipients (LTR) and as a predictive biomarker prior to different causes of graft dysfunction. Plasma from single and multicenter LTR cohorts was analyzed for dd-cfDNA. Phenotypes of treated biopsy-proven acute rejection (AR, N = 57), normal function (TX, N = 94), and acute dysfunction no rejection (ADNR; N = 68) were divided into training and test sets. In the training set, dd-cfDNA was significantly different between AR versus TX (AUC 0.95, 5.3% cutoff) and AR versus ADNR (AUC 0.71, 20.4% cutoff). Using these cutoffs in the test set, the accuracy and NPV were 87% and 100% (AR vs. TX) and 66.7% and 87.8% (AR vs. ADNR). Blood samples collected serially from LTR demonstrated incremental elevations in dd-cfDNA prior to the onset of graft dysfunction (AR > ADNR), but not in TX. Dd-cfDNA also decreased following treatment of rejection. In conclusion, the serial elevation of dd-cfDNA identifies pre-clinical graft injury in the context of normal liver function tests and is greatest in rejection. This biomarker may help detect early signs of graft injury and rejection to inform LTR management strategies.

Keywords: biomarker; clinical research/practice; immunobiology; liver allograft function/dysfunction; liver transplantation/hepatology; molecular biology: DNA; monitoring: immune; rejection: acute; translational research/science.

© 2021 The American Society of Transplantation and the American Society of Transplant Surgeons.

References

REFERENCES

    1. Demetris AJ, Bellamy C, Hübscher SG, et al. 2016 Comprehensive Update of the Banff Working Group on Liver Allograft Pathology: introduction of antibody-mediated rejection. Am J Transplant. 2016;16(10):2816-2835.
    1. Charlton M, Levitsky J, Aqel B, et al. International liver transplantation society consensus statement on immunosuppression in liver transplant recipients. Transplantation. 2018;102(5):727-743.
    1. Starzl T. Immunosuppressive therapy and tolerance of organ allografts. N Engl J Med. 2008;358(4):407-411.
    1. Dogan N, Husing-Kabar A, Schmidt HH, Cicinnati VR, Beckebaum S, Kabar I. Acute allograft rejection in liver transplant recipients: incidence, risk factors, treatment success, and impact on graft failure. J Int Med Res. 2018;46(9):3979-3990.
    1. Levitsky J, Goldberg D, Smith AR, et al. Acute rejection increases risk of graft failure and death in recent liver transplant recipients. Clin Gastroenterol Hepatol. 2017;15(4):584-593 e582.
    1. VanWagner LB, Serper M, Kang R, et al. Factors associated with major adverse cardiovascular events after liver transplantation among a national sample. Am J Transplant. 2016;16(9):2684-2694.
    1. VanWagner LB, Lapin B, Levitsky J, et al. High early cardiovascular mortality after liver transplantation. Liver Transpl. 2014;20(11):1306-1316.
    1. Vanwagner LB, Bhave M, Te HS, Feinglass J, Alvarez L, Rinella ME. Patients transplanted for nonalcoholic steatohepatitis are at increased risk for postoperative cardiovascular events. Hepatology. 2012;56(5):1741-1750.
    1. Rubín A, Sánchez-Montes C, Aguilera V, et al. Long-term outcome of ‘long-term liver transplant survivors'. Transpl Int. 2013;26(7):740-750.
    1. Watt KD, Pedersen RA, Kremers WK, Heimbach JK, Charlton MR. Evolution of causes and risk factors for mortality post-liver transplant: results of the NIDDK long-term follow-up study. Am J Transplant. 2010;10(6):1420-1427.
    1. Golestaneh L, Alvarez PJ, Reaven NL, et al. All-cause costs increase exponentially with increased chronic kidney disease stage. Am J Manag Care. 2017;23(10 Suppl):S163-S172.
    1. Gonwa TA, Mai ML, Melton LB, et al. End-stage renal disease (ESRD) after orthotopic liver transplantation (OLTX) using calcineurin-based immunotherapy: risk of development and treatment. Transplantation. 2001;72(12):1934-1939.
    1. Levitsky J, O'Leary JG, Asrani S, et al. Protecting the kidney in liver transplant recipients: practice-based recommendations from the American Society of Transplantation Liver and Intestine Community of Practice. Am J Transplant. 2016;16(9):2532-2544.
    1. Lo YM, Tein MS, Pang CC, Yeung CK, Tong KL, Hjelm NM. Presence of donor-specific DNA in plasma of kidney and liver-transplant recipients. Lancet. 1998;351(9112):1329-1330.
    1. Bloom RD, Bromberg JS, Poggio ED, et al. Cell-free DNA and active rejection in kidney allografts. J Am Soc Nephrol. 2017;28(7):2221-2232.
    1. Huang E, Sethi S, Peng A, et al. Early clinical experience using donor-derived cell-free DNA to detect rejection in kidney transplant recipients. Am J Transplant. 2019;19(6):1663-1670.
    1. Sigdel T, Archila F, Constantin T, et al. Optimizing detection of kidney transplant injury by assessment of donor-derived cell-free DNA via massively multiplex PCR. J Clin Med. 2018;8(1):19.
    1. Kataria A, Kumar D, Gupta G. Donor-derived cell-free DNA in solid organ transplant diagnostics: indications, limitations, and future directions. Transplantation. 2021;105(6):1203-1211.
    1. Khush KK. Clinical utility of donor-derived cell-free DNA testing in cardiac transplantation. J Heart Lung Transplant. 2021;40(6):397-404.
    1. Gondi KT, Kao A, Linard J, et al. Single-center utilization of donor-derived cell-free DNA testing in the management of heart transplant patients. Clin Transplant. 2021;35(5):e14258.
    1. Agbor-Enoh S, Shah P, Tunc I, et al. Cell-free DNA to detect heart allograft acute rejection. Circulation. 2021;143(12):1184-1197.
    1. Khush KK, Patel J, Pinney S, et al. Noninvasive detection of graft injury after heart transplant using donor-derived cell-free DNA: a prospective multicenter study. Am J Transplant. 2019;19(10):2889-2899.
    1. Yoshino O, Muralidharan V, Dobrovic A, Goh SK. Elevated plasma levels of cell-free DNA during liver transplantation are associated with activation of coagulation. Liver Transpl. 2020;26(4):602-603.
    1. Goh SK, Do H, Testro A, et al. The measurement of donor-specific cell-free DNA identifies recipients with biopsy-proven acute rejection requiring treatment after liver transplantation. Transplant Direct. 2019;5(7):e462.
    1. Schütz E, Fischer A, Beck J, et al. Graft-derived cell-free DNA, a noninvasive early rejection and graft damage marker in liver transplantation: a prospective, observational, multicenter cohort study. PLoS Med. 2017;14(4):e1002286.
    1. Zhao D, Zhou T, Luo YI, et al. Preliminary clinical experience applying donor-derived cell-free DNA to discern rejection in pediatric liver transplant recipients. Sci Rep. 2021;11(1):1138.
    1. Levitsky J, Asrani SK, Schiano T, et al. Discovery and validation of a novel blood-based molecular biomarker of rejection following liver transplantation. Am J Transplant. 2020;20(8):2173-2183.
    1. Levitsky J, Kandpal M, Guo K, et al. Prediction of liver transplant rejection with a biologically relevant gene expression signature [published online ahead of print July 22, 2021]. Transplantation. 2021.
    1. Banff schema for grading liver allograft rejection: an international consensus document. Hepatology. 1997;25(3):658-663.
    1. Siddiqui MB, Patel S, Bhati C, et al. Range of normal serum aminotransferase levels in liver transplant recipients. Transplant Proc. 2019;51(6):1895-1901.
    1. Sharon E, Shi H, Kharbanda S, et al. Quantification of transplant-derived circulating cell-free DNA in absence of a donor genotype. PLoS Comput Biol. 2017;13(8):e1005629.
    1. Mukaka MM. Statistics corner: a guide to appropriate use of correlation coefficient in medical research. Malawi Med J. 2012;24(3):69-71.
    1. Kurian SM, Whisenant T, Mas V, et al. Biomarker guidelines for high-dimensional genomic studies in transplantation. Transplantation. 2017;101(3):457-463.
    1. Levitsky J, Feng S. Tolerance in clinical liver transplantation. Hum Immunol. 2018;79(5):283-287.
    1. Benítez C, Londoño M-C, Miquel R, et al. Prospective multicenter clinical trial of immunosuppressive drug withdrawal in stable adult liver transplant recipients. Hepatology. 2013;58(5):1824-1835.
    1. Feng S, Ekong UD, Lobritto SJ, et al. Complete immunosuppression withdrawal and subsequent allograft function among pediatric recipients of parental living donor liver transplants. JAMA. 2012;307(3):283-293.
    1. De Simone P, Nevens F, De Carlis L, et al. Everolimus with reduced tacrolimus improves renal function in de novo liver transplant recipients: a randomized controlled trial. Am J Transplant. 2012;12(11):3008-3020.
    1. Teperman L, Moonka D, Sebastian A, et al. Calcineurin inhibitor-free mycophenolate mofetil/sirolimus maintenance in liver transplantation: the randomized spare-the-nephron trial. Liver Transpl. 2013;19(7):675-689.
    1. Shaked A, DesMarais MR, Kopetskie H, et al. Outcomes of immunosuppression minimization and withdrawal early after liver transplantation. Am J Transplant. 2019;19(5):1397-1409.
    1. Banff Working Group on Liver Allograft Pathology. Importance of liver biopsy findings in immunosuppression management: Biopsy monitoring and working criteria for patients with operational tolerance. Liver Transpl. 2012;18(10):1154-1170.
    1. Demetris AJ, Isse K. Tissue biopsy monitoring of operational tolerance in liver allograft recipients. Curr Opin Organ Transplant. 2013;18(3):345-353.
    1. Nilles KM, Levitsky J. Donor-specific antibodies in liver transplantation. Clin Liver Dis. 2020;15(1):13-16.
    1. Levitsky J, Kaneku H, Jie C, Walsh RC, Abecassis M, Tambur AR. Donor-specific HLA antibodies in living versus deceased donor liver transplant recipients. Am J Transplant. 2016;16(8):2437-2444.
    1. O'Leary JG, Demetris AJ, Friedman LS, et al. The role of donor-specific HLA alloantibodies in liver transplantation. Am J Transplant. 2014;14(4):779-787.
    1. Kourkoumpetis T, Levitsky J. Immunosuppressive drug levels in liver transplant recipients: impact in decision making. Semin Liver Dis. 2019;39(4):414-421.
    1. Levitsky J. Next level of immunosuppression: drug/immune monitoring. Liver Transpl. 2011;17(Suppl 3):S60-65.
    1. Kowalski RJ, Post DR, Mannon RB, et al. Assessing relative risks of infection and rejection: a meta-analysis using an immune function assay. Transplantation. 2006;82(5):663-668.
    1. Kamei H, Masuda S, Nakamura T, et al. Impact of glutathione S-transferase T1 gene polymorphisms on acute cellular rejection in living donor liver transplantation. Transpl Immunol. 2013;28(1):14-17.
    1. Gomez-Mateo J, Marin L, Lopez-Alvarez MR, et al. TGF-beta1 gene polymorphism in liver graft recipients. Transpl Immunol. 2006;17(1):55-57.
    1. Bohne F, Martínez-Llordella M, Lozano J-J, et al. Intra-graft expression of genes involved in iron homeostasis predicts the development of operational tolerance in human liver transplantation. J Clin Invest. 2012;122(1):368-382.
    1. Karimi MH, Daneshmandi S, Pourfathollah AA, et al. Association of IL-6 promoter and IFN-gamma gene polymorphisms with acute rejection of liver transplantation. Mol Biol Rep. 2011;38(7):4437-4443.
    1. Moya-Quiles MR, Alvarez R, Miras M, et al. Impact of recipient HLA-C in liver transplant: a protective effect of HLA-Cw*07 on acute rejection. Hum Immunol. 2007;68(1):51-58.
    1. Sindhi R, Higgs BW, Weeks DE, et al. Genetic variants in major histocompatibility complex-linked genes associate with pediatric liver transplant rejection. Gastroenterology. 2008;135(3):830-839.
    1. Evans PC, Smith S, Hirschfield G, et al. Recipient HLA-DR3, tumour necrosis factor-alpha promoter allele-2 (tumour necrosis factor-2) and cytomegalovirus infection are interrelated risk factors for chronic rejection of liver grafts. J Hepatol. 2001;34(5):711-715.
    1. Hanvesakul R, Spencer N, Cook M, et al. Donor HLA-C genotype has a profound impact on the clinical outcome following liver transplantation. Am J Transplant. 2008;8(9):1931-1941.
    1. Toby TK, Abecassis M, Kim K, et al. Proteoforms in peripheral blood mononuclear cells as novel rejection biomarkers in liver transplant recipients. Am J Transplant. 2017;17(9):2458-2467.
    1. Joshi D, Salehi S, Brereton H, et al. Distinct microRNA profiles are associated with the severity of hepatitis C virus recurrence and acute cellular rejection after liver transplantation. Liver Transpl. 2013;19(4):383-394.
    1. Fan H, Li LX, Han DD, Kou JT, Li P, He Q. Increase of peripheral Th17 lymphocytes during acute cellular rejection in liver transplant recipients. Hepatobiliary Pancreat Dis Int. 2012;11(6):606-611.
    1. Farid WRR, Pan Q, van der Meer AJP, et al. Hepatocyte-derived microRNAs as serum biomarkers of hepatic injury and rejection after liver transplantation. Liver Transpl. 2012;18(3):290-297.
    1. Massoud O, Heimbach J, Viker K, et al. Noninvasive diagnosis of acute cellular rejection in liver transplant recipients: a proteomic signature validated by enzyme-linked immunosorbent assay. Liver Transpl. 2011;17(6):723-732.
    1. Shaked A, Chang B-L, Barnes MR, et al. An ectopically expressed serum miRNA signature is prognostic, diagnostic, and biologically related to liver allograft rejection. Hepatology. 2017;65(1):269-280.
    1. Jucaud V, Shaked A, DesMarais M, et al. Prevalence and impact of de novo donor-specific antibodies during a multicenter immunosuppression withdrawal trial in adult liver transplant recipients. Hepatology. 2019;69(3):1273-1286.
    1. Bonaccorsi-Riani E, Pennycuick A, Londoño M-C, et al. Molecular characterization of acute cellular rejection occurring during intentional immunosuppression withdrawal in liver transplantation. Am J Transplant. 2016;16(2):484-496.
    1. Ramji A, Yoshida EM, Bain VG, et al. Late acute rejection after liver transplantation: the Western Canada experience. Liver Transpl. 2002;8(10):945-951.
    1. Uemura T, Ikegami T, Sanchez EQ, et al. Late acute rejection after liver transplantation impacts patient survival. Clin Transplant. 2008;22(3):316-323.
    1. Thurairajah PH, Carbone M, Bridgestock H, et al. Late acute liver allograft rejection; a study of its natural history and graft survival in the current era. Transplantation. 2013;95(7):955-959.
    1. Londoño M-C, Souza LN, Lozano J-J, et al. Molecular profiling of subclinical inflammatory lesions in long-term surviving adult liver transplant recipients. J Hepatol. 2018;69(3):626-634.
    1. Feng S, Bucuvalas JC, Demetris AJ, et al. Evidence of chronic allograft injury in liver biopsies from long-term pediatric recipients of liver transplants. Gastroenterology. 2018;155(6):1838-1851.

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