Redefining Cardiac Antibody-Mediated Rejection With Donor-Specific Antibodies and Graft Dysfunction
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Published on: May 8, 2020
Jason F Goldberg1,2,3, Xin Tian3,4, Ann Bon5
1Inova Schar Heart and Vascular, Falls Church, VA (J.F.G., P.S.).
Insights
Heart transplant recipients with donor-specific antibodies (DSAs) and graft dysfunction, even without biopsy-confirmed rejection, face increased risks. Identifying these patients early is crucial for better outcomes and survival.
Area of Science:
- Cardiology
- Transplant Immunology
- Biomarker Research
Background:
- Heart transplant recipients with donor-specific antibodies (DSAs) are at higher risk for antibody-mediated rejection.
- Many patients with graft dysfunction and DSAs lack definitive evidence of antibody-mediated rejection on endomyocardial biopsy (EMB).
Purpose of the Study:
- To evaluate the clinical significance of donor-specific antibodies (DSAs) combined with graft dysfunction in heart transplant recipients.
- To assess the association between antibody-mediated rejection categories and long-term clinical outcomes, including death and left ventricular dysfunction.
Main Methods:
- A prospective, multicenter study involving serial endomyocardial biopsies (EMB), echocardiograms, DSA monitoring, and donor-derived cell-free DNA (dd-cfDNA) evaluations.
- Outcomes were defined as positive pathological antibody-mediated rejection (pAMR+) or DSA with left ventricular (LV) dysfunction (LVEF drop ≥10% to ≤50%).
- Cox regression analysis was used to determine the association between rejection categories and adverse clinical outcomes.
Main Results:
- Donor-specific antibodies (DSAs) were present in 40% of patients.
- Median %dd-cfDNA was significantly higher in patients with pAMR+ or DSA+/LV dysfunction compared to those without.
- Both pAMR+ and DSA+/LV dysfunction were significantly associated with increased risk of death or prolonged LV dysfunction, with DSA+/LV dysfunction showing a substantially higher hazard ratio.
Conclusions:
- Expanding the definition of antibody-mediated rejection to include patients with DSAs and concurrent allograft dysfunction is critical.
- Patients with DSAs and graft dysfunction, even without biopsy-proven rejection, are at significant risk for adverse outcomes, including death.
- Early identification of these high-risk patients is essential for improved management and long-term survival in heart transplantation.
Background:
Heart transplant recipients with donor-specific antibodies (DSAs) have an increased risk for antibody-mediated rejection. However, many patients with graft dysfunction and DSA do not have evidence of antibody-mediated rejection by endomyocardial biopsy (EMB).
Methods:
Participants from this prospective, multicenter study underwent serial EMB, echocardiogram, DSA, and donor-derived cell-free DNA evaluations. Outcomes were defined as pAMR+ (pAMR≥1) or DSA+/left ventricle (LV) dysfunction (DSA presence+LVEF drop ≥10% to an LVEF≤50%). Cox regression evaluated the association between antibody-mediated rejection categories and death or sustained (for 3 months) reduction of LVEF to <50%.
Results:
Two hundred sixteen patients (29% women, 39% Black race, median age 55 [interquartile range, 47-62] years) had 1488 EMB, 2792 DSA, 1821 echocardiograms, and 1190 donor-derived cell-free DNA evaluations. DSAs were present in 86 patients (40%). Fourteen patients had isolated pAMR+ episodes and 8 patients had isolated DSA+/LV dysfunction episodes; 2 patients had pAMR+ and then subsequently DSA+/LV dysfunction with pAMR+. Median %dd-cfDNA was significantly higher at diagnosis of pAMR+ (0.63% [interquartile range, 0.23-2.0]; P=0.0002), or DSA+/LV dysfunction (0.40% [interquartile range, 0.36-1.24]; P<0.0001), compared with patients without these outcomes (0.01% [interquartile range, 0.0001-0.10]). Both pAMR+ and DSA+/LV dysfunction were associated with long-term clinical outcome of death (n=18) or prolonged LV dysfunction (n=10): pAMR+ (hazard ratio, 2.8 [95% CI, 1.03-7.4]; P=0.043); DSA+/LV dysfunction (hazard ratio, 26.2 [95% CI, 9.6-71.3]; P<0.001); composite of both definitions (hazard ratio, 6.5 [95% CI, 2.9-14.3]; P<0.001). Patients who developed pAMR+ or DSA+/LV dysfunction within the first 6 months of transplant were more likely to die within 3 years posttransplant (hazard ratio, 3.9 [95% CI, 1.03-14.6]; P=0.031).
Conclusions:
Expanding the characterization of antibody-mediated rejection to include patients with DSA and concurrent allograft dysfunction identified DSA+ patients at risk for death and prolonged LV dysfunction.
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