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Increased Negative Impact of Donor HLA-Specific Together With Non-HLA–Specific Antibodies on Graft Outcome

Reinsmoen, Nancy L.1,6; Lai, Chih-Hung1; Mirocha, James2; Cao, Kai3; Ong, Geraldine1; Naim, Mehrnoush1; Wang, Qi1; Haas, Mark4; Rafiei, Matthew5; Czer, Lawrence5; Patel, Jignesh5; Kobashigawa, Jon5

doi: 10.1097/01.TP.0000436927.08026.a8
Clinical and Translational Research

Background: De novo donor HLA-specific (dnDSA) and non-HLA antibodies including antiangiotensin type 1 receptor antibodies (AT1R-abs) have been associated with antibody-mediated rejection (AMR) and decreased graft survival as well as cellular-mediated rejection (CMR) and early onset of microvasculopathy in heart transplantation. The aim of our study was to determine the impact of anti–AT1R-ab and anti–donor HLA–specific antibody (DSA) on clinical outcomes.

Methods: Pretransplant and posttransplant sera from 200 recipients transplanted between May 2007 and August 2011 were tested for DSA (Luminex-based single antigen bead assay) and AT1R-ab (enzyme-linked immunosorbent assay). Two cutoff levels (≥17 and ≥12 units) were used to define high and intermediate binding of AT1R-ab. Clinical parameters examined were 5-year AMR/CMR (≥grade 2), coronary artery vasculopathy, and survival.

Results: At 2 years after transplant, freedom from AMR and/or CMR was 95.4% for those with no DSA (n=175), 66.9% for those with dnDSA (n=19), and 25% for those with DSA at transplant (n=6) (P<0.0001). Neither ≥17 nor ≥12 units of pretransplant levels indicated a significant difference in freedom from AMR and/or CMR. When both dnDSA and AT1R-ab ≥17 or ≥12 units were considered, freedom from AMR and/or CMR decreased to 50% and 45% (P<0.0001), respectively. Coronary artery vasculopathy and survival were not significantly impacted.

Conclusions: These results show the increased negative impact of dnDSA and AT1R-ab on freedom from AMR and/or CMR and an increased hazard ratio when both parameters are considered. Both HLA- and non-HLA–specific antibodies seem to impact graft outcome in heart transplantation.

1 HLA Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA.

2 Biostatistics Core, Research Institute and General Clinical Research Center and Cardiothoracic Surgery, Cedars-Sinai Medical Center, Los Angeles, CA.

3 MD Anderson Medical Center, Houston, TX.

4 Pathology, Cedars-Sinai Medical Center, Los Angeles, CA.

5 Cedars-Sinai Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA.

6 Address correspondence to: Nancy L. Reinsmoen, Ph.D., D(ABHI) HLA Laboratory, Cedars-Sinai Medical Center, 8723 Alden Dr, SSB # 197, Los Angeles, CA 90048.

This research was funded by Cedars-Sinai Medical Center Grant no. 217136.

J.K. received research grants (as principal investigator) from XDx, Inc. and Novartis Pharma and provides consultation (as part of the Steering Committee/Data Safety Monitoring) to TransMedics, Inc., XDx, Inc., and Novartis Pharma.

All the other authors declare no conflicts of interest.

E-mail: ReinsmoenN@cshs.org

N.L.R., C.H.L., J.P., and J.K. participated in the research design, writing of the article, performance of the research, and data analysis. J.M. and M.H. participated in the writing of the paper, performance of the research, and data analysis. K.C. participated in the research design, performance of the research, and data analysis. G.O., M.N., Q.W., and L.C. participated in the performance of the research. M.R. participated in the performance of the research and data analysis.

Received 10 June 2013. Revision requested 2 July 2013.

Accepted 9 September 2013.

Accepted October 25, 2013

© 2014 by Lippincott Williams & Wilkins