Science Frontier: Regarding dd-cfDNA, what was discussed at the ATC meeting? (1)

Due to the COVID-19 pandemic in 2020, the American Transplant Congress (ATC), originally scheduled for May 30 to June 3 in Philadelphia, was held online for the first time, presenting cutting-edge research progress in the field to transplant experts worldwide. The program covered multiple hot topics and major clinical challenges, among which the transplant liquid biopsy track featured presentations from 51 organ transplant centers'33 relevant research reports。

Judging from the research content of ATC in the past three years, organ transplant liquid biopsy (donor-derived cell-free DNA, dd-cfDNA) has become a current research hotspot. There are 51 related studies from North American organ transplant centers (18-20 years), accounting for 77%, among which theCedars-Sinai medical center in Los Angeleshas the largest number of studies (14 articles).

What are the highlights of the research on dd-cfDNA at this annual meeting? The editor will give you a detailed introduction in three issues. Let’s take a look at the selected excerpts of this issue first.

01

Zhang H, Nast CC, Huang E, Ammerman N, Vo AA, Jordan SC, Toyoda M. Donor Derived Cell Free DNA (dd-cfDNA) and Gene Expression Signatures of Antibody-Mediated Rejection (ABMR) May Improve Accuracy of ABMR Diagnosis (Dx) [abstract]. Am J Transplant. 2020; 20 (suppl 3).

Studies from transplant centers such as Cedars-Sinai Medical Center have shown that dd-cfDNA has important clinical significance for early diagnosis of antibody-mediated rejection (ABMR). This study combined dd-cfDNA detection and the expression score (GS) of ABMR-related genes (KLRF1, SH2D1B, CCL3 and CCL4) to explore whether the accuracy of diagnosing ABMR can be improved.

The results show,Both dd-cfDNA and GS have good performance in diagnosing ABMR.. Among the 20 patients with active ABMR and chronic active ABMR diagnosed by puncture, 19 had dd-cfDNA>1%, 17 had GS>0.43, and a total of 16 cases were consistent with both. GS test values ​​are more sensitive to anti-ABMR treatment. In addition, the combination of GS and dd-cfDNA can predict the occurrence of ABMR early (previous negative needle biopsy or cell-mediated rejection alone).

02

DePasquale E, Kobashigawa J, Pinney S, Khush K. dd-cfDNA as a Risk Factor for Initiating De-Novo Donor Specific Antibodies in Heart Transplantation [abstract]. Am J Transplant. 2020; 20 (suppl 3).

In kidney and lung transplant studies, it has been shown that dd-cfDNA content in recipients increases before de-novo DSA is produced. Research from Keck Hospital of USC and others aims to understand whether dd-cfDNA is related to the generation of de-novo DSA after heart transplantation.

A total of 67 heart transplant patients and 284 samples were enrolled in this study (samples that experienced rejection were excluded). The results showed that the dd-cfDNA content in DSA-negative patients was significantly lower than that in DSA-positive patients (P<0.001), while the dd-cfDNA content in patients with de-novo DSA was higher than that in patients with pre-existing DSA (P=0.001). It shows that the generation of de-novo DSA is related to dd-cfDNA, but the molecular mechanism and related clinical significance of this phenomenon need further study, because not all DSA are related to poor prognosis.

03

Waide M, Carmody J, Restaino IG. Donor-Derived Cell-Free DNA (dd-cfDNA) Levels in Stable Pediatric Kidney Transplant Recipients [abstract]. Am J Transplant. 2020; 20 (suppl 3).

In adult kidney transplant patients, dd-cfDNA has been proven to be a highly sensitive biomarker for diagnosing rejection and is widely used clinically. However, there is still a lack of research data on dd-cfDNA in the diagnosis of renal transplant rejection in children. Pediatric kidney transplant specialists from Eastern Virginia Medical School studied changes in dd-cfDNA levels in pediatric kidney transplant patients.

This study enrolled 26 pediatric kidney transplant patients, all of whom were in stable condition and had no rejection. The detection results showed that the median dd-cfDNA was 0.2% (IQR 0.12-0.32%), and the coefficient of variation was the same as previously reported in adult kidney transplant patients.To determine the rejection threshold (cut-off value) of dd-cfDNA in pediatric kidney transplant patients, positive patients need to be enrolled.

04

Guo L, Wang R, Lv J, Shen J, Wu J, Chen J. Prognostic Value of Dd-cfDNA Assay in Acute Renal Rejection Therapy: A Prospective Cohort Study [abstract]. Am J Transplant. 2020; 20 (suppl 3).

It is still unclear whether dd-cfDNA can be used to detect the therapeutic effect of rejection. The Kidney Disease Center of the First Affiliated Hospital of Zhejiang University enrolled 28 patients with acute rejection and detected the changes in blood dd-cfDNA content before and after rejection treatment. The results showed that the dd-cfDNA content in the patient's blood dropped from 2.566±0.549% to 0.773±0.116% (P < 0.001).It shows that dd-cfDNA can be used to detect rejection and evaluate the treatment effect.In addition, the use of methylprednisolone affects the content of dd-cfDNA.

05

Stites E, Kumar D, Olaitan O, Gupta G. Utility of dd-cfDNA in TCMR 1A and Borderline Allograft Rejection [abstract]. Am J Transplant. 2020; 20 (suppl 3).

The value of blood dd-cfDNA for the early diagnosis of T cell-mediated rejection (TCMR) is unclear.

A study from the University of Colorado et al. performed dd-cfDNA testing on 79 patients diagnosed with TCMR IA or borderline rejection (Banff 2017) by needle biopsy from June 2017 to May 2019 in 11 transplant centers. Stratified by dd-cfDNA >0.5% and <0.5%. Patients with dd-cfDNA >0.5% were associated with poor prognosis (GFR, p=0.0040 and de novo DSA, p<0.0001), and were also associated with future rejection or persistent rejection (p=0.0028).Based on these results, dd-cfDNA can reflect a more complete manifestation of rejection heterogeneity and provide more valuable clinical reference information on the risk of damage, thereby better understanding the prognosis of kidney transplantation.

In the next issue, the editor will continue to pay attention to the research progress of dd-cfDNA in the field of transplantation on ATC.