Introduction: Endomyocardial biopsy (EMB) is although critical for monitoring rejection of heart allografts; no consensus exists for routine surveillance biopsy (RSB) protocol yet. With improvements in therapy, the incidence of clinically significant acute cellular rejection (ACR) has decreased, but the rate of false-negative biopsy has not changed. Some of these cases likely represent AMR with minimal or no histologic findings. This study aimed to understand the importance of the histopathological C4d findings of the routine surveillance biopsies in cardiac recipients with symptomatic or asymptomatic rejection.
Materials and Methods: The study includes both the protocol and indication biopsies of 80 patients. Total 818 EMB reevaluated and classified according to the ISHLT grading system. All biopsies already stained with C4d, CD68, CD3, CD31, and HLA-DR in work routine. The expression of C4d graded as grade 1 (<10% of capillaries) and grade 2 (>10% of capillaries,). Biopsies classified into four groups according to the clinical symptoms and presence of the histologic findings of both ACR and AMR. Group A: symptomatic, EMB (+) (n: 18, 2.2%), Group B: symptomatic, EMB (-) (n: 21, 2.6%), Group C: asymptomatic, EMB (+) (n: 180, 22%), Group D: asymptomatic, EMB (-) (n: 599, 73.2%).
Results: Among 18 biopsies in Group A, 8 had AMR, 7 had ACR, and 3 had mix rejection (MXR). Total ten biopsies with AMR and MXR in Group A showed grade 2 C4d expression. DSA was positive in all these cases. Of 7 biopsies with ACR, 4 had grade 1 C4d, and neither of them had DSA. Although Group B cases did not have histological findings, C4d was found in 11 of 21 (52.4%) biopsies and 4 of 11 cases showed DSA positivity. In Group C, 11 diagnosed as AMR, 148 as ACR and 21 as MXR. All 32 biopsies with AMR and MXR had grade 2 C4d positivity, only 20 of them had DSA investigation with all 20 had positive results. Also 60 of 148 biopsies (40.5%) with ACR had grade 1 C4d positivity and out of 60 cases 50 were analyzed for DSA and 48 showed positive results. In group D, 55 showed Grade 1 C4d positivity and all of them DSA positive. Only 46 of remaining 544 biopsies in group D also had DSA, although they did not have C4d expression. In summary, the rate of DSA positivity was 61%, 19%, 37.8 and 9.2% for Group A, B, C and D, respectively. All groups showed significant difference between each other in regards to DSA positivity (p<.05).
Conclusion: This study showed the importance of pathological findings of the RSB in the monitoring cardiac rejection of recipients with or without symptoms. We conclude that C4d staining at any degree has significance for detection of AMR in cardiac allograft. We suggested that similar to kidney transplant, even one capillary staining with C4d can be a critical finding for decision of AMR and therefore the new therapy modality to prevent subclinical and subpathological AMR episodes and subsequent cardiac allograft vasculopathy in cardiac transplants.