Donor-Derived Cell-Free DNA Stratifies Risk of Mortality and Graft Dysfunction in Severe Acute Cardiac Allograft Rejection

  1. Zaid N. Safiullah
  2. Han Su
  3. Hyesik Kong
  4. Moon Kyoo Jang
  5. Keyur Shah
  6. Gerald J. Berry
  7. Palak Shah
  8. Hannah A. Valantine
  9. Xin Tian
  10. Sean Agbor-Enoh
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Abstract

Background

Cardiac acute rejection (AR) is a risk factor for poor outcomes, however there are limited risk prediction models to stratify patients for death or sustained LV dysfunction. This study assesses the prognostic utility of percentage donor-derived cell-free DNA (%dd-cfDNA) at the diagnosis of AR for poor outcomes.

Methods

The prospective multicenter GRAfT study enrolled heart transplant recipients and collected serial plasma samples to quantitate %dd-cfDNA. AR was defined as acute cellular rejection (ACR), antibody-mediated rejection (AMR), as well as biopsy-negative AMR (donor-specific antibody positivity with LV dysfunction). AR was classified as mild-to-moderate (ACR grade 2 or AMR grade 1) or severe (ACR grade ≥3, AMR grade ≥2, or DSA+/LV dysfunction) and further stratified by a %dd-cfDNA threshold of 0.25%. Regression models assessed the association between AR and %dd-cfDNA levels at the AR diagnosis with the primary composite outcome of sustained LVEF decline <50% and/or death.

Results

The study included 275 patients and 3,190 %dd-cfDNA assessments. Over the median of 4.6 (IQR 1.8 - 5.0) years follow-up, 51 patients experienced the composite outcome of death or prolonged EF reduction, and 75 patients developed AR, including 16.2% patients with ACR, 9.4% with pathologic AMR, and 6.6% with DSA+/LV dysfunction. Thirty-two (42.7%) patients had severe AR and 43 (57.3%) had mild-to-moderate AR. Severe—but not mild-to-moderate— AR was associated with an increased risk of the primary composite endpoint (HR = 5.17, 95% CI 2.38 − 11.3, p < 0.001). Among those with severe AR, a %dd-cfDNA level greater than 0.25% at diagnosis was associated with a higher risk of the primary outcome (HR, 6.06, 95% CI, 1.78– 20.6; p = 0.004). Percent dd-cfDNA remained elevated in severe AR patients with adverse outcomes.

Conclusion

Severe AR with high %dd-cfDNA levels is associated with an increased risk of poor outcomes, offering novel prognostic utility.

Clinical Perspective

What is New?

  • Percent donor-derived cell-free DNA (%dd-cfDNA) can risk stratify cardiac transplant patients with severe acute rejection for death and/or prolonged EF reduction

  • Percent dd-cfDNA remain persistently elevated in patients with severe acute rejection who develop poor outcomes, which could reflect ineffective treatment.

  • In the contemporary era of cardiac transplantation, acute rejection defined by biopsy or by donor specific antibodies plus LV dysfunction is associated with poor outcomes

What are the Clinical Implications?

  • Percent dd-cfDNA could serve as a bedside tool to risk stratify patients with severe acute rejection for poor outcomes.

  • Trends of %dd-cfDNA could serve to monitor response to treatment for severe acute rejection.

  • Percent dd-cfDNA levels at diagnosis of rejection could be leveraged for patient selection in clinical trials to test novel therapies or treatment strategies.

Article activity feed

  1. Version published to 10.1101/2025.09.15.25335831 on medRxiv