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The introduction of tacrolimus has shown decreased rates of acute and steroid-resistant rejection after liver transplantation (LTx). The aim of the present study is to examine the long-term efficacy and safety of tacrolimus in primary liver transplant recipients. The first 121 consecutive adults (aged >16 years) who underwent primary LTx at a single center from August 1989 to February 1990 were followed up until August 1997. The mean follow-up was 93.2 ± 1.2 months (range, 90.5 to 96.5 months). Patient survival, graft survival, rate of rejection, and adverse events were examined. The actual 7-year patient survival rate was 67.8%, and the graft survival rate was 63.6%. Infections, recurrence of disease, de novo malignancies, and cardiovascular events constituted the main causes of graft loss and death in the long term. Graft loss related to acute or chronic rejection was rare. The rate of acute rejection beyond 2 years was approximately 3% per year, and most rejections were steroid responsive. Approximately 70% of the patients received only tacrolimus after 1 year. Four patients developed end-stage renal disease, and 2 patients underwent kidney transplantation. Hyperkalemia and hypertension were observed in one third of the patients. New-onset insulin-dependent diabetes mellitus was observed in 9% and 13% of the patients at the 1-year and 7-year follow-up, respectively. Seven patients developed de novo malignancies, including two skin malignancies. Six patients developed posttransplantation lymphoproliferative disorder during the entire follow-up period. Actual patient and graft survival at 7 years was excellent, and few adverse events developed after the first year. Graft loss from acute or chronic rejection was rare under tacrolimus, and approximately 70% of the patients were steroid free on tacrolimus monatherapy after the first year after LTx.
Tacrolimus is a macrolide isolated from the soil fungus, Tsukubaensis. It is a potent immunosuppressive agent. The first clinical trial with tacrolimus began at our institution in March 1989, initially as rescue treatment for failing liver allo-grafts under cyclosporine (CsA).1-3 Subsequently, its use was evaluated by Todo et al4,5 in primary liver transplantation (LTx). Reduced episodes of acute rejection were shown by 1990.6,7 Three large prospective randomized trials were conducted: the University of Pittsburgh,8 the United States multicenter, and European multicenter trials comparing tacrolimus with CsA.9-11 Significantly lower rates of rejection and steroid-resistant rejection were shown in all three trials. Little is known, however, about the long-term impact of tacrolimus in liver transplant recipients.
The present study reports the long-term results of tacrolimus-based immunosuppression in primary adult liver transplant recipients with more than 90 months of follow-up. It examines patient survival, graft survival, causes of death, causes of retransplantation, rates of rejection, treatment of rejection, baseline immunosuppression, and adverse events.
This study includes the first 121 consecutive adults (aged >16 years) who underwent primary LTx under tacrolimus-based immunosuppression between August 1989 and February 1990, There were 68 men and 53 women with a mean age of 46.3 ± 12.3 years. Ninety-eight patients (81%) were hospital bound at the time of LTx. All patients were followed up until August 31, 1997. The mean follow-up was 93.2 ± 1.2 months (range, 90.5 to 96.5 months). The indications for LTx are listed in Table 1. Our immunosuppressive protocol has been previously described.6-8 The doses of tacrolimus used in this initial trial were three to five times greater than the current dosages.8-11 All palients in this population received tacrolimus, 0.15 mg/kg intravenously, on the first day and then 0.075 mglkg twice daily over 2 to 4 hours as a constant infusion.6,7 All intravenous tacrolimus has been administered as a continuous infusion at our institution since February 1991. Oral doses were administered when a patient could tolerate oral fluids. Adjustments in tacrolimus dosage were made on an individual basis, depending on the state of renal and liver function and the presence of rejection, infection, and neurotoxicity. The first 53 patients received 1 g of methylprednisone after perfusion of the liver, followed by a total of 600 mg of methylprednisone tapered over the next 5 postoperative days, starting with 200 mg on the first day (divided into four doses) and reduced to 40 mg/d over the next 4 days. The remaining 68 patients received only 20 mg of methylprednisone.6, 7.
The diagnosis of rejection was determined by an increase in serum bilirubin and hepatic enzyme levels in the absence of any technical complication, ischemic injury, or development of hepatitis (hepatitis B, hepatitis C, or cytomegalovirus). All patients also underwent protocol liver biopsies between postoperative days 10 and 14.6-8,11 Episodes of acute rejection were treated with 1 g of hydrocortisone or 1 g of methylprednisone with or without 600 mg of methylprednisone tapered over the next 5 days. Steroid-resistent rejections were treated with OKT3, 10 mL, over 5 to 7 days.
Patient and graft survival rates are shown in Figure 1. Mortality was more prominent in the first year after LTx. Thereafter, it averaged 3% every year, with an actual patient survival rate of 67.8% and graft survival rate of 63.6% at 7 years. Causes of death are shown in Table 2. Infection was the most common cause of death, particularly during the first year. Thereafter, recurrence of disease, de novo malignancies, and cardiovascular events constituted important causes of death. In 2 patients, the cause of death could not be established; both died suddenly and unexpectedly at home with normal liver function.
Twenty patients lost their first graft and underwent a second transplantation. Seven patients required a third transplant, and 2 patients needed a fourth transplant. Primary nonfunction, hepatic artery thrombosis, and recurrence of disease were the most common indications for retransplantation (Table 3).
The highest incidence of rejection occurred in the first 3 months after LTx. The rates of rejection, as listed in Table 4, progressively decreased over time from 45% in the first 3 months to 18% from 3 to 12 months, 13% in the second year, and 2% per year after the second year.
Fifty-four episodes of rejection requiring treatment occurred between 3 and 84 months after LTx in 52 patients. These episodes were controlled with l-g boluses of methylprednisone in 42 instances (78%) and l-g boluses of hydrocortisone in 12 instances (22%). One patient also received OKT3. Two primary grafts were lost because of acute and chronic rejection. Three second transplants were lost because of acute rejection in 1 patient and chronic rejection in 2 patients during the entire study period.
Liver function test results in all surviving patients were stable. The mean serum bilirubin, alanine aminotransferase, aspartate aminotransferase, gama glutamyl transferase (GGT), and alkaline phosphate levels at each year are shown in Table 4.
The mean tacrolimus dose was less each year and decreased from 0.15 mg/kg/d during the first year to 0.04 mg/kg/d at vear 7. Similarly, mean plasma tacrolimus trough concentrations were 0.76 ng/mL at 1 year and 0.5 ng/mL at 4 years. Since August 1994, we measured trough whole-blood tacrolimus concentrations, and mean concentrations were 8.8, 6.4, and 6.2 ng/mL at 5, 6, and 7 years, respectively (Table 4).
One patient, because of severe headaches, was switched to CsA in the first year and has remained on CsA. None of the patients received CsA and tacrolimus simultaneously.
Approximately 70% of the patients were maintained without prednisone. For those who received prednisone at 1 year, the dose of prednisone decreased in subsequent years. Fifteen percent of the patients were receiving greater than 5 mg/d of prednisone at 1 year, and this declined to 5% at 7 years (Table 4).
Azathioprine was not used in the first year after LTx. It was used after the first year to improve renal function by reducing the dose of tacrolimus. The number of patients receiving azathioprine varied from 8 patients during the second year to 15 patients in the seventh year. At most times, more than two thirds of the patients were receiving 50 mg/d or less of azathioprine. None of the patients received more azathioprine than 100 mg/d at any time (Table 4).
Nephrotoxicity was the most common complication of tacrolimus, as previously described. However, there was little change in the mean serum creatinine and blood urea nitrogen levels over 7 years when dialysis-dependent patients were excluded (Table 4). More than 80% of the patients had serum creatinine levels of 2.0 mg/dL or less. Two patients, however, underwent kidney transplantation for end-stage kidney disease attributable to tacrolimus toxicity at 12 and 28 months after LTx. Two other patients are currently undergOing hemodialysis.
In this population, the initial doses of tacrolimus were three to five times greater than those currently used. Transient confusional state and tremor were common; however, these complications were not properly documented. Major neurological complications have been reported on a larger population from our institution.12 The majority of neurotoxicity occurred in the immediate postoperative period and was dose dependent.
As shown in Table 4, more than 50% of the patients in the first 3 years had hyperkalemia (K+ > 5.0 mEq/L) requiring treatment. Approximately one third of the patients had hyperkalemia by 7 years (Table 4). In all cases, hyperkalemia was readily controlled with fludrocortisone.
Thirty-one percent of the patients developed new-onset hypertension, defined as the need for any hypertension medication to control blood pressure. Patients who received diuretics alone were excluded because these were administered more often for fluid retention with renal impairment at our center. In more than 75% of the patients, hypertension was controlled with a small dose of a single antihypertensive agent, usually a calcium channel blocker (Table 4).
Nine percent of the patients at 1 year and 13% of the patients at 7 years were on insulin therapy. None of these patients were known to have diabetes before transplantation (Table 4). In addition, 4 patients are currently receiving oral hypoglycemic agents.
In patients with renal impairment or hyperglycemia, there was some difference in the dosages of tacrolimus and steroids. In this population, the tacrolimus dose was usually reduced. No statistical significance, however, has been attributed to these variations.
Seven patients developed de novo malignancies, 2 of which were skin cancer (one basal cell carcinoma and another squamous cell carcinoma). Three patients developed lung cancer, 1 developed breast cancer, and 1 developed glioblastoma of the brain. The lung cancer types included one small cell, one oat cell, and one adenocarcinoma, which were diagnosed at 84, 61, and 37 months after LTx at the patient ages of 53, 49, and 67 years, respectively. These 3 patients had a history of smoking; however, 1 patient had stopped smoking 12 years before LTx.
Six patients developed posttransplantation lymphoproliferative disorders (PTLDs) involving the tonsils (2 patients), colon (2 patients), liver (1 patient), and hepatic hilum (1 patient). One patient with colonic PTLD and another with hepatic hilum PTLD received three liver transplants and had a cytotoxic-positive cross-match with donor lymphocytes. Both patients died, 1 of overwhelming cytomegalovirus infection, and the other of sepsis, respectively. The other 4 patients are currently alive and disease free (Table 4).
Introduction of CsA in the early 1980s led to major improvements in patient and graft survival, and the incidence and severity of rejection were reduced considerably.13, 14 A more potent immunosuppressive agent, tacrolimus, has contributed to further significant reductions in the number of episodes of rejection and in the severity of rejections in liver transplant recipients.8-11 Because many patients in randomized trials have been converted from CsA to tacrolimus in the event of rejection, it is not possible to evaluate the true incidence of improvement in patient and graft survival. However, a European multicenter randomized study9 and a large series from our center by Todo et al15 have shown improved patient and graft survival. The initial successes described in these initial trials appear to be sustained beyond 7 years of follow-up. Rejection rates remain low, and these episodes are readily controlled in most instances. The maintenance dose of steroids is also low, and nearly 70% of the patients are on mono therapy. Late graft losses and/or death are mostly related to a recurrence of disease (hepatitis B virus, hepatitis C virus, sclerosing cholangitis) or patient noncompliance.
In this series, all patients initially received a tacrolimus dose three to five times greater than that currently used. Long-term chronic nephrotoxicity remains a major concern; however. end-stage renal disease requiring dialysis or kidney transplantation was still less than 4% after 7.5 to 8 years of follow-up. The mean serum creatinine levels observed in this series were similar to those reported from the US Multicenter Study Group comparing CsA with tacrolimus.16 Hyperkalemia was observed in a significant number of patients and was readily controlled with fludrocortisone. Hypertension appeared to be less frequent and less severe clinically compared with published data on CsA.16,17 The incidence of new-onset insulin-dependent diabetes mellitus was 13% after 7 years in the adult population. This adverse event was not observed in children.18 Stegall et al19 reported a 13% incidence of new-onset diabetic mellitus when using CsA. Knobler et a120 reported that 23% of the patients were hyperglycemic after LTx and found no difference between CsA- and tacrolimus-based immunotherapy. De novo malignancy rates were 5.8% in the long-term follow-up. One such report on CsA after LTx by Levy et al21 reported de novo malignancy rates of 4.5%, with a mean follow-up of 35 months.21 We have published a similar incidence of 5.7% in the larger population taking tacrolimus, which compares that risk with the nontransplant population matched for age, sex, and length of follow-up.22 Six patients (5%) developed PTLD in our series, and these patients tended to receive higher doses of tacrolimus. The rate of PTLD in the larger population taking tacrolimus is 1.9% for adults and 11.4% for children, as reported from our center. 23 This rate is similar to that reported using CsA.24
In conclusion, the benefits of tacrolimus observed in the initial clinical trials are sustained in the long term. Approximately 70% of the patients can be maintained on monotherapy. Primary graft loss caused by either acute or chronic rejection is rare under tacrolimus-based immunosuppression. The overall toxicity of tacrolimus is not worse than that reported with CsA.