Significance of C4d staining in ABO-identical/compatible liver transplantation

Abstract

Complement degradation product C4d has become an important marker of humoral or antibody-mediated rejection in renal and heart allograft biopsies. Although there have been several reports on the detection of C4d in liver allografts, the significance of C4d in liver transplantation and its relationship with humoral rejection are still not clear. We investigated the frequency and pattern of C4d staining in liver allograft biopsies with reference to preoperative lymphocyte crossmatch tests, which detect donor-reactive lymphocyte antibody. Survival rates at 5 years were 77% for crossmatch-negative patients and 53% for crossmatch-positive patients (P ¼ 0.009). In crossmatch-negative patients, reproducible positive staining was obtained in 28 of 86 (33%) biopsies taken within 90 days after transplantation and 33 of 96 (34%) biopsies 90 days or after transplantation. Most C4d staining was observed in the portal areas, and no clear correlation was observed between C4d positivity and histological diagnosis. In crossmatch-positive patients, 9 of 11 (82%) biopsies showed positivity for C4d. C4d stained perivenular areas as well as portal areas. Histology of crossmatch-positive patients included acute rejection and cholangitis, but did not include periportal changes that were seen in humoral rejection in ABO-incompatible liver transplantation. In summary, focal C4d deposition was seen in various types of liver allograft injury and had little clinical impact on crossmatch-negative patients, but extensive C4d staining in crossmatch-positive patients may be associated with humoral rejection and poor graft survival.

Antibody-mediated rejection in liver transplantation: Current controversies and future directions

“…In day 7 protocol biopsy samples, we observed that diffuse C4d deposition in all compartments of the liver was seen only in recipients with concomitant circulating DSAs, regardless of the preoperative cross-match status. 24 In LDLT, diffuse perivenular, sinusoidal, lobular, and stromal C4d staining was more often observed in cross-match-positive recipients, 42 although this does not seem to correlate with the incidence of acute rejection or CR. 25 Among pediatric LDLT recipients with protocol biopsy samples obtained at least 10 years after the operation, no significant difference in C4d deposition was observed between the recipients with circulating DSAs and the recipients without circulating DSAs.…”

“…For example, the staining of hepatocytes with C4d antibodies is observed as a result of ischemia/reperfusion injury, 41 and it is not an antibody-mediated injury marker. Diffuse portal C4d staining can be seen in up to two-thirds of biopsy samples with ACR, 21,42 although a recent report demonstrated that there is no difference between cases of ACR with or without diffuse C4d deposition with respect to the Banff grade of rejection or liver enzymes. 23 Several studies have looked at the differences in the location of C4d deposition between DSA-positive and DSA-negative liver transplant recipients.…”

“…Arterial, portal venous, and sinusoidal endothelial C4d staining is more frequently observed in cross-match-positive recipients. 41,42 This deposition seems to occur readily because sinusoidal C4d staining can be seen 2 hours after reperfusion in cross-match-positive patients. 43 Within 21 days, diffuse C4d staining is significantly more common in cross-match-positive recipients.…”

Complement component 4d immunohistochemistry in the assessment of liver allograft biopsy samples: Applications and pitfalls

“…It is absolutely necessary to compare biopsy samples of dysfunctional tissue with normal control livers and allografts with different diagnoses. Many studies have reported a high rate of C4d positivity in various locations of the liver and with various diagnoses (see Table 2 in Sakashita et al 7 as well as Bellamy et al 8 and Hori et al 9 ). Hori et al reported that 23 of 27 ABO-incompatible living donor liver transplants showed C4d positivity in the portal endothelium, and they did not mention sinusoidal staining.…”

The Diagnosis of Acute Antibody-Mediated Rejection in ABO-Incompatible Liver Transplants

“…Focal deposition of C4d in liver is found in a variety of conditions and is generally regarded as of little clinical impact. There are reports that show extensive C4d deposition is associated with AMR and correlated with graft survival (10). However, C4d deposition in liver has been reported in several other conditions, such as acute cellular rejection, chronic rejection, recurrent diseases including auto- Fig.…”