How To Use Serial C4d and C3d in the Diagnosis of Antibody Mediated Rejection vs. Accommodation: 51 Month Experience with 550 Heart Transplant Patients
E Rene Rodriguez, Carmela D Tan. Cleveland Clinic, Cleveland, OH
Background: We have shown that serial assessment of C4d and C3d allows accurate diagnosis of antibody mediated rejection (AMR) in heart transplants, with high positive predictive value and high correlation to donor the presence of specific antibody (DSA) and clinical symptoms. In addition there is high mortality in the C4d+ C3d+ patients. However, the meaning C4d deposition alone is difficult to interpret by pathologists.
Design: All endomyocardial biopsies from October 2006 to December 2010 (51 months) were stained for C4d and C3d by immunofluorescence. A total of 4876 biopsies from 520 adult patients (age 20-73) were reviewed. There were 405 males and 115 females. An average of 13 biopsies per patient were examined. Electronic medical records were queried for: 1. Allograft dysfunction; 2. Serologic evidence of anti HLA antibodies; 3. Evidence of cardiac allograft vasculopathy (CAV).
Results: Thirty six (7%) of 520 patients were positive for C4d and C3d, diffuse in capillaries and 42 (8%) of 520 were positive for diffuse C4d only. Thirty three were focally positive for C4d only. There were no C3d positive only patients in this cohort. Histologic features of AMR were seen in 36% of biopsies. The median time for conversion of negative biopsy to positive for complement deposition was 30 months for C4d+ / C3d+ patients. The median for C4d+ diffuse was 10 months and for C4d+ focal was 15 months. Diffuse C4d positivity when examined in serial biopsies is mostly fortuitous and not associated with allograft dysfunction. Focal positive C4d is not correlated with DSA or dysfunction over time. There was no significant correlation found between the number of positive biopsies and mortality. Only 6 of 42 diffuse C4d+ cases evolved to show DSA and dysfunction. Thirty six of 42 diffuse C4d+ cases showed no dysfunction, despite the presence of DSA in 6 of them. Thus interpreted as accommodation.
Conclusions: Serial staining of biopsies shows that: 1. Concomitant C4d and C3d positivity correlates highly with allograft dysfunction and DSA; 2. Diffuse C4d capillary staining alone should not be equated with AMR; 3. Most C4d+ episodes are single occurrences and asymptomatic; 4. The presence of C4d staining and DSA without allograft dysfunction may indicate accommodation; 5. Only a small fraction of patients with C4d staining alone may develop AMR on follow-up.
Wednesday, March 21, 2012 1:00 PM
Poster Session VI # 35, Wednesday Afternoon