Clinical Perspective of Acute Humoral Rejection After Blood Type-Compatible Liver Transplantation

Acute humoral rejection (AHR) is antibody-mediated rejection caused by complement activation and antibodies against the donor graft, and it usually occurs immediately (hyperacute) or during the first week (acute) after organ transplantation (1). The liver allograft has been considered relatively resistant to immunologic rejection, and most liver graft rejections are cellular rejections (2). Although AHR is well described in blood type-incompatible liver transplantation (LT) (3), its occurrence in blood type-compatible LT is an uncommon complication. Clinically, AHR diagnosis currently relies on histologic findings, presence of donor-specific antibodies, and graft dysfunction (1, 4). However, early detection and treatment of AHR after LT remains uncertain. Among 316 LTs, 6 patients (1.9%) had AHR within 2 weeks after LT (range 5–14 days). Table 1 summarizes the clinical features of AHR patients after LT. All patients first presented with rapid increase of liver enzymes, which increased by 2- or 3-fold every 6 hr (see Figure 1A, Supplemental Digital Content 1,https://links.lww.com/TP/A348). However, increased liver enzymes levels were refractory to pulse therapy and recycling steroids. Main portal vein stenosis or thrombosis were not observed; however, Doppler sonography showed a markedly decreasing portal flow (see Figure 1B, Supplemental Digital Content 1,https://links.lww.com/TP/A348). Furthermore, examination of artery flow revealed no significant variation. Tissue biopsies of liver grafts for histologic examinations were obtained from three patients; all demonstrated massive coagulative necrosis of the liver parenchyma and occluded small branches of portal vessels. However, no inflammatory cell infiltration existed in the remaining portal tracts, and immunohistochemical examinations were all positive for C4d deposition in vessel walls. These finding indicate that the deterioration of liver function was not because of vascular complication but likely related to AHR.TABLE 1: Clinical features of patients with AHR after liver transplantationFive (83%) of six patients with AHR died because of inappropriate management, and only one patient was successfully rescued by early plasmapheresis combined with bortezomib therapy. At the start of AHR, this patient also exhibited extensive increase of liver enzymes, followed by decreased portal flow. Therefore, plasmapheresis was performed, and bortezomib was administered in cases highly suspicious for AHR. After treatment, liver function and portal flow stopped deteriorating and then improved (see Figure 2, Supplemental Digital Content 2,https://links.lww.com/TP/A349). The patient was alive with normal liver function at study end. DISCUSSION AHR after blood type-compatible LT is uncommon, and most existing literature for AHR is individual case reports (5–7). Thus, the real incidence of AHR after LT may be underestimated as diagnosing AHR early during the postoperative period is difficult. Herein, this report described our limited experience with, and collected information regarding, clinical presentations and outcomes that may prove helpful in treating AHR patients after LT. All patients had the same identical clinical course characterized by sudden onset of sharply increased liver enzymes levels accompanied by a dramatic decrease in portal flow during early stage of AHR. Deterioration of liver function was also refractory to intravenous bolus steroid therapy, which is in contrast to acute cellular rejection that can be managed successfully with a short course of high-dose steroids. In addition, analyses of the liver biopsy samples usually reveal characteristic features such as portal edema, periportal hemorrhage and necrosis, or deposition of immune complex components in the sinusoids of portal tracts. The deposition of immune complex components followed by occlusion of small branches of portal vessels would be reflected in clinical presentations of increased portal vein resistance, leading to decreased portal flow; notably, hepatic artery inflow was less affected because of its higher blood pressure. Subsequently, a marked decrease in portal flow and deterioration of allograft liver function may be observed during late-stage AHR. Currently, the treatment strategy for AHR associated with LT remains uncertain because of its rarity and is generally based on accumulated experiences for AHR cases that were managed successfully in renal transplantation (8–11). Bortezomib is a proteasome inhibitor, and its antiplasma cell properties and suppression of function of T-cell lymphocytes have shown to be effective in treating mixed antibody- and cellular-mediated rejection after renal transplantation (12–14), leading us to the use of bortezomib as a novel approach for treating AHR in patient. However, the timing of therapeutic intervention for AHR is extremely important. Several reports indicated that therapeutic intervention should be started as soon as AHR is suspected (6, 7). When therapeutic intervention is started late, AHR can result in allograft loss and can be fatal. Therefore, therapeutic intervention with plasmapheresis to remove circulating antibodies in addition to other novel treatment regimens to reduce antibody production should be considered as soon as AHR is clinically suspected to treat patients during the reversible stage. Kun-Ming Chan1 Ching-Sung Lee2 Ting-Jung Wu1 Chen-Fang Lee1 Tse-Ching Chen3 Wei-Chen Lee1 1 Department of General Surgery, Chang Gung Transplantation Institute Chang Gung Memorial Hospital at Linkou Chang Gung University College of Medicine Taoyuan, Taiwan 2 Department of Gastroenterology Chang Gung Memorial Hospital at Linkou Chang Gung University College of Medicine Taoyuan, Taiwan 3 Department of Pathology Chang Gung Memorial Hospital at Linkou Chang Gung University College of Medicine Taoyuan, Taiwan