Jonathan S Bromberg1, Daniel C Brennan2, Emilio Poggio3, Suphamai Bunnapradist4, Anthony Langone5, Puneet Sood6, Arthur J Matas7, Roslyn B Mannon8, Shikha Mehta8, Asif Sharfuddin9, Bernard Fischbach10, Mohanram Narayanan11, Stanley C Jordan4,12, David J Cohen13, Ziad S Zaky3, David Hiller14, Robert N Woodward15, Marica Grskovic15, John J Sninsky15, James P Yee16, Roy D Bloom17. 1. Department of Surgery, Division of Transplantation, University of Maryland, Baltimore, MD. 2. Division of Nephrology, Washington University School of Medicine, St. Louis, MO. 3. Department of Nephrology and Hypertension, Cleveland Clinic, Cleveland, OH. 4. Department of Medicine, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA. 5. Department of Medicine, Vanderbilt University Medical Center, and Medical Specialties Clinic, Veteran Affairs Hospital Renal Transplant Program, Nashville, TN. 6. Thomas Starzl Transplant Institute, University of Pittsburgh Medical Center, Pittsburgh, PA. 7. Division of Transplantation, Department of Surgery, University of Minnesota, Minneapolis, MN. 8. Division of Nephrology, Department of Medicine, and Division of Transplantation, University of Alabama School of Medicine, Birmingham, AL. 9. Division of Nephrology and Transplant, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN. 10. Baylor Research Institute, Dallas, TX. 11. Division of Nephrology and Hypertension, Texas A&M Health Science Center College of Medicine, Temple, TX. 12. Division of Nephrology, Cedars-Sinai Medical Center, Los Angeles, CA. 13. Department of Surgery, Columbia University Medical Center, New York, NY. 14. Biostatistics. 15. Research and Development, and. 16. Clinical Research, CareDx, Inc., Brisbane, CA. 17. Department of Medicine, University of Pennsylvania, Perelman School of Medicine and Penn Kidney Pancreas Transplant Program, Pennsylvania, PA.
Abstract
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.
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.
Authors: Michael Oellerich; Karen Sherwood; Paul Keown; Ekkehard Schütz; Julia Beck; Johannes Stegbauer; Lars Christian Rump; Philip D Walson Journal: Nat Rev Nephrol Date: 2021-05-24 Impact factor: 28.314
Authors: Theresa K Wolf-Doty; Roslyn B Mannon; Emilio D Poggio; Randall J Hinojosa; David Hiller; Jonathan S Bromberg; Daniel C Brennan Journal: Kidney360 Date: 2021-02-03
Authors: Michael Kueht; Katie Kirk; A Scott Lea; Heather L Stevenson; Jeff Fair; A Kathleen Gamilla-Crudo; Syed Hussain; Muhammad Mujtaba Journal: Hum Immunol Date: 2022-07-14 Impact factor: 2.211
Authors: Yousuf Kyeso; Anshul Bhalla; Alyssa P Smith; Yaqi Jia; Safa Alakhdhair; Stephanie C Ogir; Mohammad Abuzeineh; Daniel C Brennan; Sami Alasfar Journal: Transplant Direct Date: 2021-05-25