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Absolute Quantification of Donor-Derived Cell-Free DNA as a Marker of Rejection and Graft Injury in Kidney Transplantation - Results From a Prospective Observational Study

Michael Oellerich, Maria Shipkova, Thomas Asendorf, Philip D Walson, Verena Schauerte, Nina Mettenmeyer, Mariana Kabakchiev, Georg Hasche, Hermann-Josef Gröne, Tim Friede, Eberhard Wieland, Vedat Schwenger, Ekkehard Schütz, Julia Beck
American Journal of Transplantation 2019 May 7
Donor-derived cell-free DNA (dd-cfDNA) is a non-invasive biomarker for comprehensive monitoring of allograft injury and rejection in kidney transplantation (KTx). dd-cfDNA quantification of copies/mL plasma [dd-cfDNA(cp/mL)] was compared to dd-cfDNA fraction [dd-cfDNA(%)] at pre-specified visits in 189 patients over one year post KTx. In patients (N=15, n=22 samples) with biopsy-proven rejection (BPR), median dd-cfDNA(cp/mL) was 3.3-fold and median dd-cfDNA(%) 2.0-fold higher (82cp/mL; 0.57% respectively) than medians in Stable Phase patients (N=83, n=408) without rejection (25cp/mL; 0.29%). Results for ATN were not significantly different from those with BPR. dd-cfDNA identified unnecessary biopsies triggered by a rise in plasma creatinine. ROC analysis showed superior performance (p=0.02) of measuring dd-cfDNA(cp/mL) (AUC=0.83) compared to dd-cfDNA(%) (AUC=0.73). Diagnostic odds ratios were 7.31 for dd-cfDNA(cp/mL), and 6.02 for dd-cfDNA(%) at thresholds of 52cp/mL and 0.43% respectively. Plasma creatinine showed a low correlation (r=0.37) with dd-cfDNA(cp/mL). In a patient subset (N=24) there was a significantly higher rate of patients with elevated dd-cfDNA(cp/mL) with lower tacrolimus levels (<8μg/L) compared to the group with higher tacrolimus concentrations (p=0.0036) suggesting that dd-cfDNA may detect inadequate immunosuppression resulting in subclinical graft damage. Absolute dd-cfDNA(cp/mL) allowed for better discrimination than dd-cfDNA(%) of KTx patients with BPR and is useful to avoid unnecessary biopsies. This article is protected by copyright. All rights reserved.


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