The significance of donor-specific HLA antibodies in rejection and ductopenia development in ABO compatible liver transplantation.

The role of humoral alloreactivity in ABO-compatible liver transplantation remains unclear. To understand the significance of donor-specific HLA alloantibodies (DSA) in liver rejection, we applied the currently used strategy for detection of antibody-mediated rejection of other solid allografts. For this purpose we reviewed the data on 43 recipients of ABO identical/compatible donor livers who had indication liver biopsy stained for complement element C4d and contemporaneous circulating DSA determination. Seventeen (40%) patients had significant circulating DSA in association with diffuse portal C4d deposition (DSA+/diffuse C4d+). These DSA+/diffuse C4d+ subjects had higher frequency of acute cellular rejection (ACR) 15/17 versus 13/26 (88% vs. 50%), p = 0.02, and steroid resistant rejection 7/17 versus 5/26 (41% vs. 19%), p = 0.03. Based on detection of the combination DSA+/diffuse C4d+, 53.6% of cases of ACR had evidence of concurrent humoral alloreactivity. Six of the 10 patients with ductopenic rejection had circulating DSA and diffuse portal C4d, three of whom (2 early and 1 late posttransplantation) developed unrelenting cholestasis, necessitating specific antibody-depleting therapy to salvage the allografts. Thus, in ABO-compatible liver transplantation humoral alloreactivity mediated by antibodies against donor HLA molecules appears to be frequently intertwined with cellular mechanisms of rejection, and to play a role in ductopenia development.

The impact of donor variables on the outcome of orthotopic liver transplantation for hepatitis C.

Morphologic characteristics of the graft have been proposed as a major contributor to the long-term outcomes in orthotopic liver transplantation (OLT). Our objective was to determine the impact of donor variables, including donor age, donor-recipient HLA match, and type of donation (DCD vs donation after brain death [DBD]), on the outcome of OLT in 192 patients with hepatitis C virus (HCV). Fourteen patients underwent OLT from donation after cardiac death (DCD) donors and 188 from DBD donors. Mean donor age, warm ischemia time at recovery, and cold ischemia time were similar between the groups. Overall graft survival rate at 1 year (55% DCD vs 85% DBD) and 5 years (46% DCD vs 78% DBD) was significantly lower in the DCD group (P = .0003). Similarly, patient survival rate at 1 year (62% DCD vs 93% DBD) and 5 years (62% DCD vs 82% DBD) was significantly lower in the DCD group (P = .0295). Incidences of hepatic artery thrombosis, portal vein thrombosis, and primary nonfunction were similar between the DCD and DBD groups. The incidence of liver abscess with ischemic-type biliary stricture was higher in recipients from DCD as compared with DBD (42% vs 2%). A trend toward lower graft survival was noted in recipients from donors older than 60 years of age in the HCV population (P = .07), with statistically lower patient survival (P = .02). Donor- recipient HLA matching did not appear to correlate with OLT outcome in patients with HCV. DCD donors and donors older than 60 years of age significantly impact patient and graft survival. Lower graft and patient survival in recipients from DCD donors does not appear to be related to early disease recurrence.

Analysis of tumor characteristics and survival in liver transplant recipients with incidentally diagnosed hepatocellular carcinoma.

The use of orthotopic liver transplantation (OLTX) for the treatment of hepatocellular carcinoma (HCC) has generally become restricted to carefully selected cases of small oligocentric tumors. However, it is not uncommon to find previously undetected HCC within recipient cirrhotic livers at the time of hepatectomy. The impact of unsuspected HCC on patient outcomes remains unclear. A retrospective analysis of our institutional experience with adult primary OLTX was performed comparing recipients with incidental HCC (group 1), recipients with known or suspected HCC (group 2), and recipients confirmed by pathologic examination to be tumor free (group 3). Between 1984 and 2000, 27 patients in group 1, 12 patients in group 2, and 612 patients in group 3 underwent primary OLTX. Tumors were smaller (P = 0.0172) in group 1 than in group 2; however, the number of tumors and the histologic findings were similar in the groups. Incidence of bilobar involvement, vascular invasion, portal vein tumor thrombus, lymphatic involvement, and distant metastasis at the time of OLTX did not differ significantly between these groups. Four-year patient survival appeared to be lower in group 1 (70.0%) than in group 3 (79.0%) (P = 0.0546); 4-year patient survival was significantly worse in group 2 (31.0%) compared to group 3 (P = 0.0106). Thus, in our experience, incidentally diagnosed cases of HCC possess many of the same features of malignancy as preoperatively diagnosed HCC. Indeed, patient survival after OLTX appears to be adversely affected by the presence of incidental HCC.

Reestablishment of cell polarity of rat hepatocytes in primary culture.

The cell-basement membrane interaction is an important determinant of epithelial cell polarity. Although hepatocytes in situ are polarized, no morphologically identifiable basement membrane is found at their basal surface. However, several studies have demonstrated immunoreactivity to basement membrane proteins in the space of Disse, indicating the existence of an extracellular matrix, albeit of low density. Therefore we hypothesized that the interaction of hepatocytes with this matrix may determine their polarity and asked whether a basement membrane-like substrate could reestablish hepatocyte polarity in vitro. For this purpose, established monolayers of primary rat hepatocytes were cultured overlaid with a basement membrane-like matrix extracted from the Engelbreth-Holm-Swarm mouse tumor, mimicking thus the in situ tissue architecture. The hepatocytes in this culture configuration, unlike hepatocytes in classic cultures, developed distinct membrane domains, as demonstrated by the reformation of gamma-glutamyltranspeptidase, Mg(2+)-ATPase-positive bile canalicular networks and intercellular gap junctions immunolocalized to the lateral membrane with antibodies to connexin 32. The actin cytoskeleton of these cells reorganized into pericanalicular webs, and no accumulation of "stress" filaments was found beneath the membrane facing the medium. Golgi complexes appeared to be preferentially located in mitochondria-poor pericanalicular cytoplasm, indicating the polarized distribution of these organelles. Together, these data indicate that a basement membrane-like substrate present between hepatocytes and nutrient medium restores the polarity of these cells in culture. Extrapolation of these findings to the intact liver suggests that the matrix in Disse's space governs the development of hepatocyte polarity.