title: Time-dependent specificity of immunopathologic (C4d-CD68) and histologic criteria of antibody-mediated rejection for donor-specific antibodies and allograft dysfunction in heart transplantation.
abstract: BACKGROUND
  In heart transplantation, antibody-mediated rejection (AMR) is diagnosed and graded on the basis of immunopathologic (C4d-CD68) and histopathologic criteria found on endomyocardial biopsies (EMB). Because some pathologic AMR (pAMR) grades may be associated with clinical AMR, and because humoral responses may be affected by the intensity of immunosuppression during the first posttransplantation year, we investigated the incidence and positive predictive values (PPV) of C4d-CD68 and pAMR grades for clinical AMR as a function of time.
  
  
  METHODS
  All 564 EMB from 40 adult heart recipients were graded for pAMR during the first posttransplantation year. Clinical AMR was diagnosed by simultaneous occurrence of pAMR on EMB, donor specific antibodies and allograft dysfunction.
  
  
  RESULTS
  One patient demonstrated clinical AMR at postoperative day 7 and one at 6 months (1-year incidence 5%). C4d-CD68 was found on 4,7% EMB with a "decrescendo" pattern over time (7% during the first 4 months vs. 1.2% during the last 8 months; P < 0.05). Histopathologic criteria of AMR occurred on 10.3% EMB with no particular time pattern. Only the infrequent (1.4%) pAMR2 grade (simultaneous histopathologic and immunopathologic markers) was predictive for clinical AMR, particularly after the initial postoperative period (first 4 months and last 8 months PPV = 33%-100%; P < 0.05).
  
  
  CONCLUSIONS
  In the first posttransplantation year, AMR immunopathologic and histopathologic markers were relatively frequent, but only their simultaneous occurrence (pAMR2) was predictive of clinical AMR. Furthermore, posttransplantation time may modulate the occurrence of C4d-CD68 on EMB and thus the incidence of pAMR2 and its relevance to the diagnosis of clinical AMR.
authors.affiliation: 1 Department of Cardiology, University Hospital Center (CHUV) and University of Lausanne, Lausanne, Switzerland. 2 Institute of Pathology, University Hospital Center (CHUV) and University of Lausanne, Lausanne, Switzerland. 3 Department of Immunology and Allergology, University Hospital Center (CHUV) and University of Lausanne, Lausanne, Switzerland. 4 Department of Heart Surgery, University Hospital Center (CHUV) and University of Lausanne, Lausanne, Switzerland. 5 Center for Organ Transplantation, University Hospital Center (CHUV) and University of Lausanne, Lausanne, Switzerland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Yerly
authors.forename: Samuel
authors.initials: S
authors.lastname: Rotman
authors.forename: Antoine
authors.initials: A
authors.lastname: Nobile
authors.forename: Vincent
authors.initials: V
authors.lastname: Aubert
authors.forename: PierGiorgio
authors.initials: P
authors.lastname: Tozzi
authors.forename: Nuray
authors.initials: N
authors.lastname: Yarol
authors.forename: Pierre
authors.initials: P
authors.lastname: Vogt
authors.forename: Roger
authors.initials: R
authors.lastname: Hullin
authors.forename: Manuel
authors.initials: M
authors.lastname: Pascual
mesh_terms: D000368:Aged; D064591:Allografts; D000906:Antibodies / Q000737:chemistry*; D015703:Antigens, CD / Q000737:chemistry*; D015214:Antigens, Differentiation, Myelomonocytic / Q000737:chemistry*; D015935:Complement C4b / Q000737:chemistry*; D005260:Female; D006084:Graft Rejection; D006333:Heart Failure / Q000276:immunology* / Q000628:therapy*; D016027:Heart Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000737:chemistry*; D011184:Postoperative Period; D012680:Sensitivity and Specificity; D013997:Time Factors; D014019:Tissue Donors; D016896:Treatment Outcome; D000097382:CD68 Molecule
chemical_list: D000906:Antibodies; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D015935:Complement C4b; D010446:Peptide Fragments; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C032261:complement C4d