Importance of Routine Antihuman/Leukocyte Antibody Monitoring
Authors: Ka L. Wong, Timucin Taner, Byron H. Smith, Sudhir S. Kushwaha, Brooks S. Edwards, Manish J. Gandhi, Walter K. Kremers, Richard C. Daly, Naveen L. Pereira
Journal: Circulation (2017)

The significance of de novo donor-specific antibodies (dnDSAs) after heart transplantation (HTx) on alloimmune injury, including acute cellular rejection (ACR), antibody-mediated rejection (AMR), and cardiac allograft vasculopathy, remains unclear.In this study, we examined the importance of routine solidphase arrays in detecting dnDSA during long-term follow-up of recipients of HTx.The study protocol was approved by the Mayo Clinic Institutional Review Board, and patients gave informed consent.Between January 2009 and December 2013, 86 of 101 consecutive adult recipients of HTx underwent routine serial antihuman leukocyte antigen (HLA) antibody monitoring before and 1 week, 4 months, 1 year, and annually after HTx using a panel of single-antigen beads (LABScreen, One Lambda, Inc.) read on a Luminex (Luminex Corp.) platform.Mean fluorescence intensity levels ≥2000 were considered positive.According to the International Society for Heart and Lung Transplantation classification, 1546 endomyocardial biopsies scored with severe ACR defined as grade 2R or 3R.Serial 3-dimensional intravascular ultrasound examinations were performed as previously published. 1umulative incidences were estimated using the Kaplan-Meier method.Cox-proportional hazard models were used for analysis of time-to-event data.Variables with a P value <0.10 by univariable analysis were included in multivariable analyses, and dnDSA was included as a time-dependent covariate.The mean age of recipients and donors was 50±12.9 and 34±12.9years, respectively.The majority of the recipients were male (64%) and white (87%).Seventeen recipients (20%) had preexisting DSA.Twenty-nine recipients developed dnDSA (4, 22, and 3 with class I, class II, and both class I and class II dnDSA, respectively) over a follow-up of 50.5±19.7months.The average mean fluorescence intensity value of first positive dnDSA was 4076, and the mean time of dnDSA development was 13 months.Baseline characteristics, including recipient age, sex, body mass index, race, prior ventricular assist device, donor age, cytomegalovirus mismatch, HLA mismatch, panel reactive antibody, preexisting DSA, positive complement-dependent cytotoxic cross-match, positive B-cell and T-cell flow-cytometry cross-match, immunosuppressive agents, and rate of calcineurin to rapamycin conversion were similar between recipients with and without dnDSA (P>0.05).Sixteen recipients (5/16 with class I dnDSA) had ≥1 episode of AMR, and 26 recipients (12/26 with class II dnDSA) had ≥1 episode of severe ACR, resulting in 81% and 68% freedom from AMR and severe ACR at 5 years, respectively (Figure A andB).Patients with class I dnDSA were found to have a higher incidence of AMR (P<0.001) (Figure C), whereas patients with class II dnDSA had a higher incidence of severe ACR (P=0.012)(Figure D).Recipient female sex, preexisting DSA, positive B-cell flow-cytometry crossmatch, and class I and II dnDSA were associated with AMR in univariable analysis with P<0.10.In multivariable analysis, only class I dnDSA (hazard ratio (HR), 27.8; P<0.001) and male sex (hazard ratio, 0.14; P=0.