Antibody-mediated rejection after adult living-donor liver transplantation triggered by positive lymphocyte cross-match combination
A 46-year-old female was admitted suffering from well-developed liver cirrhosis. Hepatitis C virus infection was diagnosed at 39 years of age and she had been treated at another hospital for the last seven years. Although the number of different medications used to treat the condition (furosemide, spironolactone, ursodeoxycholic acid, lactulose, and branched-chain amino acids) and their dosages had slowly increased over the last year, her condition was not well-controlled. She had frequent episodes of esophageal variceal rupture over the last year and had suffered from intractable ascites and a right pleural effusion. Because of her deteriorating condition, she was referred to our division for LDLT. On admission, she had a low-grade fever and cell counts in the ascites and pleural effusion were 2270 /mm3 and 2580 /mm3, respectively. We diagnosed spontaneous bacterial peritonitis and pleuritis which were managed pre-operatively by drainage, hydration and cefotaxime i.v. The low-grade fever disappeared after treatment. Her status according to the United Network for Organ Sharing was IIB. Her scores for Child-Pugh and the model for end-stage liver disease were 14 and 25, respectively.\nPre-transplant lymphocyte cross-match tests were performed using direct complement-dependent cytotoxicity (CDC) and anti-human globulin assays (anti-human immunoglobulin lymphocytotoxicity test, AHG-LCT) [,]. The results of these tests were positive. Moreover, the patient showed strong reactions against donor HLA Class I antigens (). Also, flow cytometry (FCM) showed that the lymphocytes of the recipient were reactive against HLA Class I antigens (). The HLA typing of both the recipient and the donor is shown (). We also performed additional tests to assess the patient’s immunoreactivity to specific HLA Class I antigens. The lymphocytes of the recipient showed strong immunoreactivity against HLA Class I loci including HLA B 55. Tests showed that the donor had this HLA B locus (), which meant that the patient could potentially mount a donor-specific anti-HLA antibody response after transplantation.\nAlthough the results of the cross-matching tests were positive for this particular donor and recipient, the ABO blood group was compatible and the patient had no history of receiving blood transfusions from the donor. As we were unable to find a more suitable donor, the ethics committee of our institution granted approval for the procedure and written informed consent was obtained from both the recipient and the donor. During surgery we found that the patient had splenomegaly and developed collateral vessels (umbilical vein and coronary vein) and so we performed a splenectomy and ligation of collateral vessels to obtain improved intra-operative control of portal venous pressure. We reported that portal venous pressure <15 mmHg is a key for successful LDLT [,], and the final pressure was 13 mmHg in this case. The surgery lasted 822 minutes and intra-operative blood loss was 7700 mL. The graft was a left-lobe graft and the graft weight was 450 g. The graft:recipient weight ratio was 0.91. The patient received 24 units of red cells, 16 units of plasma and 30 units of platelets during the procedure. We used tacrolimus, methylprednisolone and mycophenolate mofetil as immunosuppressants and the trough level of tacrolimus was kept at 8–10 ng/mL during the early post-operative period. Methylprednisolone was given intravenously (1 mg/kg) once daily from post-operative Day (POD) 1 to POD 3 followed by 0.5 mg/kg once daily for the next 3 days. The dosage of mycophenolate mofetil was 10 mg/kg/d from POD 1.\nPost-operative splanchnic in-flow and out-flow were excellent as assessed by Doppler ultrasound studies. The post-operative course was uneventful until POD 3 when the patient experienced a sudden elevation of serum lactate dehydrogenase (LDH) levels, a decrease in the platelet count and severe fragmentation of red blood cells. Serum total bilirubin (T-Bil) levels were increased after POD 3 leading to a prolonged case of jaundice. On POD 4 a chest X-ray was taken and showed an acute respiratory distress syndrome-like condition. Blood gas analysis revealed significant respiratory insufficiency. The patient’s respiratory function worsened to a point where she required mechanical ventilation. Plasma exchange (PE) (80 mL/kg/d) was performed daily after POD 4 () and she received steroid pulse therapy (methylprednisolone at 10 mg/kg, i.v.) from POD 5. The gated area represented immunoreactivity against Class I antigens, and the percentages were calculated as the counts in the gated area/the whole counts. The percentages at pre-LDLT, PODs 2, 5, 6, 8 and 9 were 71.7, 1.7, 1.9, 11.2, 7.3 and 25.8 %, respectively. Although immunoreactivity against HLA Class I antigen was down-regulated during the early period after LDLT it increased again from POD 6. Note that this immunoreactivity was down-regulated on POD 5 even though graft dysfunction began on POD 3 and that this immunoreactivity remained from POD 6 even after repeated PE. On POD 8, peripheral blood examination showed evidence of hemolysis and that haptoglobin levels had fallen (<5.0 mg/dL). Percutaneous microecchymosis was noted and coagulation profiles were consistent with disseminated intravascular coagulation (DIC). The patient’s condition worsened and she did not respond to further treatment, including daily PE. On POD 9 we performed a liver needle biopsy under US guidance. Histopathological examination clearly showed severe graft damage (). We diagnosed HR mediated by an antigen-specific immune response to the donor tissue based on the clinical, immunological and histopathological findings. The patient experienced multi-organ failure accompanied by DIC and died at POD 9 despite intensive treatment.