Circulating donor-specific anti-human leukocyte antigen antibodies and complement C4d deposition are associated with the development of cardiac allograft vasculopathy

Renee Frank, Maria R Molina, Lee R Goldberg, Joyce W Wald, Malek Kamoun, Priti Lal
American Journal of Clinical Pathology 2014, 142 (6): 809-15

BACKGROUND: Cardiac allograft vasculopathy (CAV) continues to be a limiting factor in long-term survival of heart transplant recipients (HTRs). Pathophysiologic and immunologic factors affecting CAV are complex, and criteria for early diagnosis remain elusive.

METHODS: We performed a retrospective analysis of the relationship between donor-specific antibody (DSA), C4d immunofluorescence, and the development of CAV.

RESULTS: We evaluated 330 endomyocardial biopsy (EMB) specimens from 112 cardiac grafts. Twenty-four (21%) of 112 grafts developed CAV, and 18 (75%) of 24 were positive for C4d. Patients with DSA (n = 51) against human leukocyte antigen class I (n = 5), II (n = 26), or both (n = 20) developed CAV at a rate of 40%, 38%, and 20% and a mean time to CAV of 89, 47, and 25 months, respectively. Of 61 grafts without DSA, only 13% developed CAV, with a mean time to CAV of 116 months.

CONCLUSIONS: Compared with the general HTR population, patients with graft dysfunction and DSA or positive C4d on EMB show a statistically significant increased incidence of CAV and allograft failure, suggesting an antibody-mediated injury. The presence of pre- and posttransplant DSA, even in the absence of positive C4d immunofluorescence, may identify a group of HTRs at increased risk of developing CAV.

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