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. 2020 Sep;20(9):2491-2498.
doi: 10.1111/ajt.15822. Epub 2020 Mar 10.

High levels of dd-cfDNA identify patients with TCMR 1A and borderline allograft rejection at elevated risk of graft injury

Erik Stites  1 , Dhiren Kumar  2 , Oyedolamu Olaitan  3 , Sidney John Swanson  4 , Nicolae Leca  5 , Matthew Weir  6 , Jonathan Bromberg  7 , Joseph Melancon  8 , Irfan Agha  9 , Hasan Fattah  10 , Tarek Alhamad  11 , Yasir Qazi  12   13 , Alexander Wiseman  1 , Gaurav Gupta  2
Affiliations

High levels of dd-cfDNA identify patients with TCMR 1A and borderline allograft rejection at elevated risk of graft injury

Erik Stites et al. Am J Transplant. 2020 Sep.

Abstract

The clinical importance of subclinical, early T cell-mediated rejection (Banff TCMR 1A and borderline lesions) remains unclear, due, in part to the fact that histologic lesions used to characterize early TCMR can be nonspecific. Donor-derived cell-free DNA (dd-cfDNA) is an important molecular marker of active graft injury. Over a study period from June 2017 to May 2019, we assessed clinical outcomes in 79 patients diagnosed with TCMR 1A/borderline rejection across 11 US centers with a simultaneous measurement of dd-cfDNA. Forty-two patients had elevated dd-cfDNA (≥0.5%) and 37 patients had low levels (<0.5%). Elevated levels of dd-cfDNA predicted adverse clinical outcomes: among patients with elevated cfDNA, estimated glomerular filtration rate declined by 8.5% (interquartile rate [IQR] -16.22% to -1.39%) (-3.50 mL/min/1.73 m2 IQR -8.00 to -1.00) vs 0% (-4.92%, 4.76%) in low dd-cfDNA patients (P = .004), de novo donor-specific antibody formation was seen in 40% (17/42) vs 2.7% (P < .0001), and future or persistent rejection occurred in 9 of 42 patients (21.4%) vs 0% (P = .003). The use of dd-cfDNA may complement the Banff classification and to risk stratify patients with borderline/TCMR 1A identified on biopsy.

Keywords: biomarker; cellular transplantation (non-islet); clinical research/practice; kidney (allograft) function/dysfunction; kidney failure/injury; monitoring: immune; rejection: T cell mediated (TCMR).

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Conflict of interest statement

The authors of this manuscript have conflicts of interest to disclose as described by the American Journal of Transplantation. Matthew Weir, Jonathan Bromberg, Oyedolamu Olaitan, Joseph Melancon, Yasir Qazi, Tarek Alhamad, and Gaurav Gupta are named speakers for CareDx.

Patients were tested with AlloSure dd‐cfDNA as part of standard care. No financial incentives were received for this project and it was done independently. There are no conflicts of interests.

Figures

Figure 1
Figure 1
Violin plot shows the probability density at different values smoothed by a kernel density estimator, where the donor‐derived cell‐free DNA (dd‐cfDNA) measurements obtained from the 52 patients diagnosed with T cell–mediated rejection 1A and 27 borderline patients are displayed with IQR and previously published thresholds of clinically significant dd‐cfDNA levels as well as the recommended significant threshold based on the distribution of the data
Figure 2
Figure 2
Donor‐derived cell‐free DNA (dd‐cfDNA) distributions. TCMR, T cell–mediated rejection [Color figure can be viewed at wileyonlinelibrary.com]
Figure 3
Figure 3
Cumulative distribution functions of the percent change in estimated glomerular filtration rate (eGFR) from diagnosis of T cell–mediated rejection (TCMR) 1A and borderline up to 6 months after event [Color figure can be viewed at wileyonlinelibrary.com]
See this image and copyright information in PMC

References

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