Can C4d immunostaining on endomyocardial biopsies be considered a prognostic biomarker in heart transplant recipients?

BACKGROUND: The aim of this study was to assess the significance of positive C4d capillary immunostaining of endomyocardial biopsies and its correlation to clinical outcome in adult heart transplant recipients. METHODS: Nine hundred eighty-five endomyocardial biopsies from 107 heart transplant recipients were evaluated. Immunostaining for detection of intragraft C4d capillary deposition was performed on paraffin-embedded tissue using anti-human C4d polyclonal antibody. RESULTS: Positive staining of C4d was present in 36 patients (34%) and antibody-mediated rejection in eight patients (7%). The patients were subdivided into four groups on the basis of their C4d, circulating antidonor antibodies (donor-specific antibodies [DSAs]), and graft function: group 1=C4d positive, DSA negative, and no graft dysfunction; group 2=C4d positive, DSA positive, and no graft dysfunction; group 3=C4d positive, DSA positive, and signs of graft dysfunction, and group 0 (control)=all negative. An higher mortality risk was found in C4d-positive patients, when compared with negative ones (unadjusted hazard ratios: group 1: 18, group 2: 61, and group 3: 32-fold risk; P<0.0001). CONCLUSIONS: Antibody-mediated rejection is a complex and ongoing phenomenon with different phenotypic features. C4d positive predicts worse prognosis. C4d positive [corrected] and DSA can be used as early mortality predictors in patients without signs of graft dysfunction.

Antibody-mediated rejection without acute graft dysfunction in adult ABO-compatible heart transplantation: a case of accommodation.

Humoral rejection in heart transplantation is associated with graft dysfunction, circulating anti-donor antibodies and C4d deposits in endomyocardial biopsies. Detecting C4d capillary positivity is of diagnostic and prognostic value. C4d positivity can be found in solid-organ transplants in cases of "accommodation," a form of humoral rejection without graft dysfunction. Accommodation might reflect a change in antibodies or in the antigen, or the graft acquiring a resistance to injury by antibodies and complement. We present a case of accommodation in the setting of adult ABO-compatible orthotopic heart transplantation, which was diagnosed according to the recently introduced ISHLT criteria for humoral rejection: despite this immunologic profile, the patient never showed signs of graft dysfunction. Physicians should be aware of the accommodation phenomenon so they can identify this subset of patients and assess its long-term effects on chronic rejection and outcome in transplanted patients.

Continuous engraftment and differentiation of male recipient Y-chromosome-positive cardiomyocytes in donor female human heart transplants.

BACKGROUND: The mechanisms of stem cell engraftment and differentiation in transplanted organs are still unknown. The aim of our study was to assess the time course of extracardiac progenitor cell colonization of cardiac allografts using the human sex-mismatched heart transplant model. The possible mechanisms by which stem cells acquire a cardiac phenotypic lineage were also investigated. METHODS: Thirty-four endomyocardial biopsies were obtained from 17 sex-mismatched orthotopic heart transplant patients (mean age, 43.50 +/- 23.95 years). Cells of recipient origin were identified by fluorescence in situ hybridization for combined XY-chromosomes. RESULTS: The mean incremental number of cardiomyocytes of recipient origin per month was 0.064 +/- 0.04, suggesting ongoing engraftment and transdifferentiation in the absence of cell fusion. Regression analysis showed a positive correlation between the Y-chromosome-positive cardiomyocytes and the rejection score (r(2) = 0.99; 95% confidence interval -0.14 + 0.02; p = 0.006) suggesting that colonization was more pronounced in cases of more severe cardiac injury. At multivariable analysis, time since transplantation was the only independent predictor of the proportion of XY-chromosome-positive cardiac cell engraftment (beta = 0.025, p < 0.0001, 95% confidence interval, 0.012-0.038). CONCLUSION: The phenotypic transformation in this human chronic heart injury model is the result of transdifferentiation of male stem cells (atrial or circulating cells) into new cardiomyocytes. Immunologic injury predicts recipient cardiomyocyte engraftment and may be one of the mobilizing stimuli.