Humoral Heart Rejection (Severe Allograft Dysfunction with no Signs of Cellular Rejection or Ischemia): Incidence, Management, and the Value of C4d for Diagnosis

Abstract

Severe allograft dysfunction after heart transplant (HT), without ischemia or evidence of cellular rejection upon endomyocardial biopsy (EMB), is a rare but potentially fatal condition that suggests humoral rejection (HR). Its incidence, and the methods of choice for its diagnosis and management, remain uncertain. We retrospectively studied 445 HT patients (April 1991-December 2003) to determine incidence of HR diagnosed by clinical and conventional histopathological criteria. We used immunofluorescence (IF) techniques to test archived frozen EMB issue for IgM, IgG, C1q, C3, fibrin and C4d. Twelve patients (2.7%) fulfilled the criteria for HR after a mean time post-HT of 21.3 ± 24.7 months (range: 2-72 months). Patients were treated with high doses of steroids and plasmapheresis, with successful recovery in 11 cases. IF studies using classical markers were mainly negative for the six patients with enough EMB tissue for testing. All six patients showed positivity for C4d during the HR episode but not before or after. Humoral rejection was observed in less than 3% of HT patients. Plasmapheresis treatment was highly effective. Classical IF tests were not useful for diagnosis, but C4d appears to be useful both for confirmation of diagnosis and for monitoring response to treatment.

C4d Deposition and Clearance in Cardiac Transplants Correlates With Alloantibody Levels and Rejection in Rats

“…These conditions resulted in diffuse, dense deposits of C4d on the capillaries throughout the myocardium. The staining of C4d in the capillaries was similar to that found in clinical endomyocardial biopsies (7,(9)(10)(11)(12). In addition, C4d deposition was found on the large arteries and veins.…”

“…It is not clear whether the IgG associated with the matrix is functional because it is not associated with C4d staining. A similar difficulty in interpreting stains for IgG has been noted in clinical endomyocardial biopsies (9,10).…”

“…C4d deposition is particularly prevalent in patients sensitized by previous transplants, pregnancies or blood transfusions. Although C4d has been widely studied in renal transplants, relatively few studies have examined the value of C4d as a correlate of antibody-mediated rejection in human cardiac transplants (9)(10)(11). In addition to C4d, Fishbein and coworkers (12) have emphasized an association between antibody-mediated rejection and accumulations of macrophages in capillaries of endomyocardial biopsies.…”

Correlation of Donor-Specific Antibodies, Complement and Its Regulators with Graft Dysfunction in Cardiac Antibody-Mediated Rejection

“…However, the reported sensitivities of endothelial cell activation and swelling at 63% and of intravascular macrophages at 30% in a large retrospective study were low (2). (3)(4)(5)(6)(7). The subsequent availability of commercial monoclonal antibodies against complement split products C4d and C3d has proven the usefulness of these markers (6,7).…”

C4d staining is a valuable marker in identifying chronic GVHD in colonic biopsies following BMT

“…1 This marker has been shown to be useful in identifying antibody mediated rejection in renal transplant biopsies and cardiac transplant biopsies. 2,3 It is unclear whether C4d-positive staining can be detected in internal organs with GVHD following BMT. We report three cases of chronic GVHD identified in colon biopsies in which dilated capillaries were all positively stained for C4d, 4 months-2 years following BMT (see Table 1; Figures 1 and 2).…”