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

Jonathan S. Bromberg, Daniel C. Brennan, Emilio Poggio, Suphamai Bunnapradist, Anthony Langone, Puneet Sood, Arthur J. Matas, Roslyn B. Mannon, Shikha Mehta, Asif Sharfuddin, Bernard Fischbach, Mohanram Narayanan, Stanley C. Jordan, David J. Cohen, Ziad S. Zaky, David Hiller, Robert N. Woodward, Marica Grskovic, John J. Sninsky, James P. YeeRoy D. Bloom

Research output: Contribution to journalArticlepeer-review

29 Scopus citations


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 Identifier: NCT02424227.

Original languageEnglish (US)
Pages (from-to)309-321
Number of pages13
JournalThe journal of applied laboratory medicine
Issue number3
StatePublished - Nov 1 2017

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© 2017 American Association for Clinical Chemistry.


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