Circulating donor-specific anti-human leukocyte antigen antibodies and complement C4d deposition are associated with the development of cardiac allograft vasculopathy.
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.
From the Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, and.
Renee
R
Frank
Heart Failure and Cardiac Transplant Program, Division of Cardiovascular Medicine, University of Pennsylvania, Philadelphia.
Maria R
MR
Molina
Heart Failure and Cardiac Transplant Program, Division of Cardiovascular Medicine, University of Pennsylvania, Philadelphia.
Lee R
LR
Goldberg
Heart Failure and Cardiac Transplant Program, Division of Cardiovascular Medicine, University of Pennsylvania, Philadelphia.
Joyce W
JW
Wald
From the Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, and.
Malek
M
Kamoun
From the Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, and.
Priti
P
Lal
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D064591:Allografts / Q000276:immunology; D000906:Antibodies / Q000276:immunology*; D015935:Complement C4b / Q000378:metabolism*; D005260:Female; D006084:Graft Rejection / Q000276:immunology* / Q000378:metabolism; D006680:HLA Antigens / Q000276:immunology*; D016027:Heart Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000378:metabolism*; D012189:Retrospective Studies; D014019:Tissue Donors; D055815:Young Adult
D000906:Antibodies; D006680:HLA Antigens; D010446:Peptide Fragments; D015935:Complement C4b; C032261:complement C4d
Acute antibody-mediated rejection; C4d; Cardiac allograft vasculopathy; Donor-specific antibodies