A total of 247 LDLTs were performed in adult patients at the University of Tokyo Hospital between January 1996 and March 2005. Among the 224 recipients, 18 patients were excluded because of death within the 6 mo. Moreover, another two cases were excluded, one who received the graft from his identical twin and another who received auxiliary partial orthotopic liver transplantation. The remaining 204 patients (102 men and 102 women; age range: 18-67 years) were enrolled in the study. The median postoperative follow-up period was 34 mo (range, 6-114). The most common indication for LDLT was viral cirrhosis (n = 77) followed by primary biliary cirrhosis (n = 46).

Pre-operative aspartate transaminase, total bilirubin levels, and serum creatinine were 19-308 IU/L, 4-400 mg/L, and 2-44 mg/L, respectively. The median score for model for end-stage liver disease was 14 (range, 4-34).

Our surgical technique for recipient and donor surgery is described elsewhere[7]. All the patients received the same immunosuppressive regimen (Table 1) consisting of tacrolimus (FK, Prograf, Astellas Pharma Inc., Tokyo, Japan) and methylprednisolone. If adverse effects occurred with FK, the patient was switched to cyclosporine (CsA). The indications for conversion are described elsewhere[8]. More than 6 mo after LDLT, FK and CsA were maintained at 5 to 10 μg/L and 100 to 150 μg/L, respectively, with therapeutic drug monitoring at least once a month. A trough level of less than 5 μg/L FK or less than 100 μg/L CsA was regarded as sub-therapeutic. Methylprednisolone was maintained at 0.05 mg/kg per day by oral administration for lifetime of the recipients after the initial 6 mo.

Diagnosis of acute rejection was based on internationally accepted histologic criteria[9]. Acute rejection occurring more than 6 mo after LDLT was regarded as LAR. Biopsy-proven acute cellular rejection scored more than 3 in Banff classification was treated with high-dose methylprednisolone (20 mg/kg per day) followed by recycling. Patients with steroid-resistant cellular rejection were treated with mycophenolate mofetil and anti-T-cell monoclonal antibody (OKT3, Ortho-Biotech Corporation, Raritan, NJ).

The cytomegalovirus status of the patient was moni-tored by pp65 antigenemia assay once a week for 3 mo postoperatively. When there were more than 5 antigen-positive cells/50 000 white blood cells, antiviral therapy was started until the antigenemia assay was negative. Details of antibacterial and antifungal prophylaxis are described elsewhere[10].

Hyperlipidemia was diagnosed when the serum cholesterol level was over 2300 mg/L in two successive examinations. Chronic renal failure was defined as serum creatinine of more than 25 mg/L on at least two successive determinations more than 6 mo after LDLT. Patients with normal glucose tolerance preoperatively, who required pharmacologic assistance to control blood sugar more than 6 mo after the transplantation, were diagnosed with new-onset post-transplantation diabetes.

The incidence of acute rejection and post-transplantation complications more than 6 mo after LDLT was examined. Preoperative factors included age, gender, disease, serum total bilirubin levels, model for end-stage liver disease score, donor/recipient blood type, gender match, donor age, and the result of donor/recipient human leukocyte antigens (HLA) and the lymphocytotoxic crossmatch. Intraoperative factors included anhepatic phase duration, blood loss, and graft weight/standard liver volumes[11]. Postoperative factors were initial immunosuppressive regimen (FK or CsA), cytomegalovirus infection, and episodes of early acute rejection.

Categorical data were compared using chi-square or Fisher’s exact tests. Continuous data were compared using the t-test or Mann Whitney U test. Multiple regression analysis was performed using the proportional hazards models to identify factors that were independently associated with LAR. The trough levels of the calcineurin inhibitors 6 mo after LDLT were recorded and compared between patients with LAR and those without. LAR-free survival was stratified by immunosuppressive regimen using the log-rank test. A P value of less than 0.05 was considered statistically significant. Values of measured variables were expressed as median and range.

None of the patients experienced immediate graft non-function or chronic rejection. Postoperative vascular, hemorrhagic, and biliary complications that required re-operation within 6 mo, occurred in 75 patients (37%). Conversion from FK to CsA was required in 38 patients (19%) during the initial 6 mo after surgery. The most common reason for conversion was neurotoxicity (n = 15), followed by hematopoietic disorder (n = 7), diabetes mellitus (n = 6), gastrointestinal intolerance (n = 4), hepatotoxicity (n = 3) and cardio-pulmonary disorder (n = 3). The median time to conversion was 16 d (range: 6-165). The cumulative 1- and 3-year patient survival rates were 90% and 87%, respectively.

Serum cholesterol and serum creatinine levels were 1130 mg/L (range, 560-2110) and 10 mg/L (range, 2-44) preoperatively, and 1850 mg/L (range, 900-3760) and 8.6 mg/L (range, 3-31) at 6 mo after transplantation, respectively. The incidence of hyperlipidemia, chronic renal failure, and new-onset post-transplantation diabetes was 13% (n = 27), 2% (n = 3), and 24% (n = 48), respectively. To date, none of the patients has developed symptomatic cardiovascular diseases or end-stage renal disease that required hemodialysis or kidney transplantation.

Positive cytomegalovirus antigenemia occurred in 40% (82/204), all within 6 mo of surgery. The incidence of deep fungal infection that occurred more than 6 mo after surgery was 17% (35/204), which included candidiasis (n = 20), aspergillosis (n = 5), Pneumocystis carinii pneumonia (n = 3), and cryptococcosis (n = 2). The median time to the diagnosis was 192 d (range: 181-326). These deep infections were all successfully treated, except for one patient who died due to cryptococcosis.

LAR was observed in 15 cases (7%, Table 2). The median time to LAR was 302 d (range: 182-1490). All LAR cases were on a maintenance dose of steroid (methylprednisolone 0.05 mg/kg per day), except for one patient who had undergone steroid withdrawal 10 mo before LAR because of aseptic necrosis of the femoral head. Univariate analysis revealed that CsA-based immunosuppressive regimen at the onset of LAR and lower recipient age were significantly associated with LAR (Table 2). Multivariate analysis revealed that only the CsA-based regimen was an independent predictor (Hazard ratio, 0.033; range, 0.007 to 0.142; P < 0.0001).

LAR-free survival stratified by immunosuppression regimen (FK-based or CsA-based) is shown in Figure 1. In those who developed LAR, only one patient in the CsA group had a sub-therapeutic level at least once during the preceding 8 wk. The trough levels more than 6 mo after transplantation were properly maintained within the target range in both FK-based and CsA-based recipients and were not related to LAR (Table 3). All LAR patients were successfully treated with steroid recycle therapy only, except for two who required additional mycophenolate mofetil and anti-T-cell monoclonal antibody administration. None of them developed chronic rejection.

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Figure 1 Kaplan-Meier plot of LAR-free survival based on immunosuppression. Thick line: patients with tacrolimus (n = 166); thin line: those with cyclosporine (n = 38). P < 0.0001 comparison between patients with tacrolimus and cyclosporine.