Diagnostic application of kidney allograft-derived absolute cell-free DNA levels during transplant dysfunction

John B. Whitlam, Ling Ling, Alison Skene, John Kanellis, Francseco L. Ierino, Howard R. Slater, Damien L. Bruno, David A. Power

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Graft-derived cell-free DNA (donor-derived cell-free DNA) is an emerging marker of kidney allograft injury. Studies examining the clinical validity of this biomarker have previously used the graft fraction, or proportion of total cell-free DNA that is graft-derived. The present study evaluated the diagnostic validity of absolute measurements of graft-derived cell-free DNA, as well as calculated graft fraction, for the diagnosis of graft dysfunction. Plasma graft-derived cell-free DNA, total cell-free DNA, and graft fraction were correlated with biopsy diagnosis as well as individual Banff scores. Sixty-one samples were included in the analysis. For the diagnosis of antibody mediated rejection, the receiver-operator characteristic area under the curves of graft-derived cell-free DNA and graft fraction were 0.91 (95% CI 0.82-0.98) and 0.89 (95% CI 0.79-0.98), respectively. Both measures did not diagnose borderline or type 1A cellular mediated rejection. Graft fraction was associated with a broader range of Banff lesions, including lesions associated with cellular mediated rejection, while graft-derived cell-free DNA appeared more specific for antibody mediated rejection. Limitations of this study include a small sample size and lack of a validation cohort. The capacity for absolute quantification, and lower barriers to implementation of this methodology recommend it for further study.

Original languageEnglish
Pages (from-to)1037-1049
Number of pages13
JournalAmerican Journal of Transplantation
Volume19
Issue number4
DOIs
Publication statusPublished - Apr 2019

Keywords

  • biomarker
  • clinical research/practice
  • diagnostic techniques and imaging
  • genetics
  • kidney (allograft) function/dysfunction
  • kidney transplantation/nephrology
  • organ transplantation in general
  • rejection
  • rejection: antibody-mediated (ABMR)
  • translational research/science

Cite this

Whitlam, John B. ; Ling, Ling ; Skene, Alison ; Kanellis, John ; Ierino, Francseco L. ; Slater, Howard R. ; Bruno, Damien L. ; Power, David A. / Diagnostic application of kidney allograft-derived absolute cell-free DNA levels during transplant dysfunction. In: American Journal of Transplantation. 2019 ; Vol. 19, No. 4. pp. 1037-1049.
@article{4b59a4ff80cc4199ae4612773ecff346,
title = "Diagnostic application of kidney allograft-derived absolute cell-free DNA levels during transplant dysfunction",
abstract = "Graft-derived cell-free DNA (donor-derived cell-free DNA) is an emerging marker of kidney allograft injury. Studies examining the clinical validity of this biomarker have previously used the graft fraction, or proportion of total cell-free DNA that is graft-derived. The present study evaluated the diagnostic validity of absolute measurements of graft-derived cell-free DNA, as well as calculated graft fraction, for the diagnosis of graft dysfunction. Plasma graft-derived cell-free DNA, total cell-free DNA, and graft fraction were correlated with biopsy diagnosis as well as individual Banff scores. Sixty-one samples were included in the analysis. For the diagnosis of antibody mediated rejection, the receiver-operator characteristic area under the curves of graft-derived cell-free DNA and graft fraction were 0.91 (95{\%} CI 0.82-0.98) and 0.89 (95{\%} CI 0.79-0.98), respectively. Both measures did not diagnose borderline or type 1A cellular mediated rejection. Graft fraction was associated with a broader range of Banff lesions, including lesions associated with cellular mediated rejection, while graft-derived cell-free DNA appeared more specific for antibody mediated rejection. Limitations of this study include a small sample size and lack of a validation cohort. The capacity for absolute quantification, and lower barriers to implementation of this methodology recommend it for further study.",
keywords = "biomarker, clinical research/practice, diagnostic techniques and imaging, genetics, kidney (allograft) function/dysfunction, kidney transplantation/nephrology, organ transplantation in general, rejection, rejection: antibody-mediated (ABMR), translational research/science",
author = "Whitlam, {John B.} and Ling Ling and Alison Skene and John Kanellis and Ierino, {Francseco L.} and Slater, {Howard R.} and Bruno, {Damien L.} and Power, {David A.}",
year = "2019",
month = "4",
doi = "10.1111/ajt.15142",
language = "English",
volume = "19",
pages = "1037--1049",
journal = "American Journal of Transplantation",
issn = "1600-6135",
publisher = "Wiley-Blackwell",
number = "4",

}

Diagnostic application of kidney allograft-derived absolute cell-free DNA levels during transplant dysfunction. / Whitlam, John B.; Ling, Ling; Skene, Alison; Kanellis, John; Ierino, Francseco L.; Slater, Howard R.; Bruno, Damien L.; Power, David A.

In: American Journal of Transplantation, Vol. 19, No. 4, 04.2019, p. 1037-1049.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Diagnostic application of kidney allograft-derived absolute cell-free DNA levels during transplant dysfunction

AU - Whitlam, John B.

AU - Ling, Ling

AU - Skene, Alison

AU - Kanellis, John

AU - Ierino, Francseco L.

AU - Slater, Howard R.

AU - Bruno, Damien L.

AU - Power, David A.

PY - 2019/4

Y1 - 2019/4

N2 - Graft-derived cell-free DNA (donor-derived cell-free DNA) is an emerging marker of kidney allograft injury. Studies examining the clinical validity of this biomarker have previously used the graft fraction, or proportion of total cell-free DNA that is graft-derived. The present study evaluated the diagnostic validity of absolute measurements of graft-derived cell-free DNA, as well as calculated graft fraction, for the diagnosis of graft dysfunction. Plasma graft-derived cell-free DNA, total cell-free DNA, and graft fraction were correlated with biopsy diagnosis as well as individual Banff scores. Sixty-one samples were included in the analysis. For the diagnosis of antibody mediated rejection, the receiver-operator characteristic area under the curves of graft-derived cell-free DNA and graft fraction were 0.91 (95% CI 0.82-0.98) and 0.89 (95% CI 0.79-0.98), respectively. Both measures did not diagnose borderline or type 1A cellular mediated rejection. Graft fraction was associated with a broader range of Banff lesions, including lesions associated with cellular mediated rejection, while graft-derived cell-free DNA appeared more specific for antibody mediated rejection. Limitations of this study include a small sample size and lack of a validation cohort. The capacity for absolute quantification, and lower barriers to implementation of this methodology recommend it for further study.

AB - Graft-derived cell-free DNA (donor-derived cell-free DNA) is an emerging marker of kidney allograft injury. Studies examining the clinical validity of this biomarker have previously used the graft fraction, or proportion of total cell-free DNA that is graft-derived. The present study evaluated the diagnostic validity of absolute measurements of graft-derived cell-free DNA, as well as calculated graft fraction, for the diagnosis of graft dysfunction. Plasma graft-derived cell-free DNA, total cell-free DNA, and graft fraction were correlated with biopsy diagnosis as well as individual Banff scores. Sixty-one samples were included in the analysis. For the diagnosis of antibody mediated rejection, the receiver-operator characteristic area under the curves of graft-derived cell-free DNA and graft fraction were 0.91 (95% CI 0.82-0.98) and 0.89 (95% CI 0.79-0.98), respectively. Both measures did not diagnose borderline or type 1A cellular mediated rejection. Graft fraction was associated with a broader range of Banff lesions, including lesions associated with cellular mediated rejection, while graft-derived cell-free DNA appeared more specific for antibody mediated rejection. Limitations of this study include a small sample size and lack of a validation cohort. The capacity for absolute quantification, and lower barriers to implementation of this methodology recommend it for further study.

KW - biomarker

KW - clinical research/practice

KW - diagnostic techniques and imaging

KW - genetics

KW - kidney (allograft) function/dysfunction

KW - kidney transplantation/nephrology

KW - organ transplantation in general

KW - rejection

KW - rejection: antibody-mediated (ABMR)

KW - translational research/science

UR - http://www.scopus.com/inward/record.url?scp=85056309480&partnerID=8YFLogxK

U2 - 10.1111/ajt.15142

DO - 10.1111/ajt.15142

M3 - Article

VL - 19

SP - 1037

EP - 1049

JO - American Journal of Transplantation

JF - American Journal of Transplantation

SN - 1600-6135

IS - 4

ER -