Steroid-Resistant Acute Rejections After Liver Transplant

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1 ARTICLE Steroid-Resistant Acute Rejections After Liver Transplant Cem Aydogan, 1 Sinasi Sevmis, 1 Sema Aktas, 1 Hamdi Karakayali, 1 Beyhan Demirhan, 2 Mehmet Haberal 1 Abstract Objectives: Liver transplant is the definitive treatment for the end-stage liver disease. Although effective immunosuppressants are available, steroid-resistant acute rejection can be encountered. Materials and Methods: Between September 2001 and April 2010, 285 adult and pediatric liver transplant were done on 279 patients from deceased donors and living-related donors at our center. All patients received tacrolimus-based immunosuppressive therapy. Steroids were tapered in 3 months. Liver biopsy was done to confirm acute rejection after vascular or biliary complications had been excluded. High-dose steroids were administered for acute rejections. If there was no response to steroids, acute rejection was defined as steroid-resistant acute rejection. After confirming steroid-resistant acute rejection by a second biopsy, antithymocyte globulin was given to patients until liver functions return to normal level with ganciclovir prophylaxis. Results: Acute rejection was detected in 87 liver transplants (30.5%). Steroid-resistant acute rejections were detected in 12 of 87 patients (7 male, 5 female; 8 pediatric, 4 adult patients; mean age, ± 12.1 years) (13.7%). Mean time from transplant to steroid-resistant acute rejection was ± days (range, days). The predominant cause of liver disease before liver transplant in patients who had steroid-resistant acute rejection was fulminant hepatic failure. From the Departments of 1 General Surgery and 2 Pathology, Baskent University Faculty of Medicine, Ankara, Turkey Address reprint requests to: Mehmet Haberal, MD, FACS, FICS(Hon), Baskent University 1. Cad. No:77, Bahcelievler 06490, Ankara, Turkey Phone: Fax: rektorluk@baskent-ank.edu.tr Experimental and Clinical Transplantation (2010) 2: Steroid-resistant acute rejection therapy was successful in 10 of 12 patients (83.3%). Two patients did not respond to therapy; therefore, they advanced to chronic rejection. Adverse effects due to cytokine release were the most frequently encountered reactions in the early period of antithymocyte globulin treatment. The mean follow-ups after steroid-resistant acute rejection treatment were 38.2 ± 26 months (range, 2-85 months). We did not encounter any serious reaction, serious infection, or long-term adverse effect after antithymocyte globulin treatment. Conclusions: According to our experience, antithymocyte globulin can be considered as a good therapeutic option in steroid-resistant acute rejection with acceptable adverse effects. Key words: Autoimmune hepatitis, Antithymocyte globulin, Fulminant hepatic failure. Introduction Liver transplant is the definitive treatment for the end-stage liver disease. Calcineurin inhibitors and steroids are the primary immunosuppressive therapy after liver transplant in many transplant centers worldwide (1). Although calcineurin inhibitors have potent immunosuppressive effects, acute cellular rejections, and chronic rejections can still be encountered in patients who are taking calcineurin inhibitors after liver transplant even after appropriate blood drug levels are achieved (1). The typical approach to acute cellular rejections involves optimization of baseline immunosuppressive therapy and high-dose steroid therapy. Twenty-eight percent to 35% of patients who have acute cellular rejections do not respond to high-dose steroid therapy and require further intervention (2, 3). The aim of this study is to retrospectively review steroid- Copyright Başkent University 2010 Printed in Turkey. All Rights Reserved.

2 Cem Aydogan et al / Experimental and Clinical Transplantation (2010) 2: resistant acute rejections that can affect outcomes directly and are a major challenge after liver transplant. Materials and Methods Two hundred eighty-five adult and pediatric liver transplants were performed for 279 patients from deceased and living-related donors for acute and chronic liver disease at Baskent University Ankara Hospital, Turkey, between September 2001 and April Acute cellular rejections were detected in 87 patients (30.5%), and steroid-resistant acute rejection was detected in 12 of these 87 patients (13.7%). We retrospectively reviewed demographic characteristics, cause of liver failure before liver transplant, results of liver function tests (before and after steroidresistant acute rejection treatment), rejection activity index according to Banff criteria (4, 5) at the time of acute cellular rejections, and steroid-resistant acute rejection, the adverse effects during steroid-resistant acute rejection treatment, and clinical outcomes of these 12 steroid-resistant acute rejection patients. The clinical outcomes of the patients were assessed as successful treatment with resolution of steroidresistant acute rejection, shown by normalization of liver function tests and improvements in the clinical condition of patients or as treatment failure owing to ongoing rejection resulting in repeat liver transplant or death. The liver function tests including total bilirubin, direct bilirubin, aspartate aminotransferase, alanine amino transferase, alkaline phosphatase, and δ- glutamyl transpeptidase were assessed biochemically. Primary immunosuppression therapy in all liver transplant recipients at Baskent University Hospital includes tacrolimus and a corticosteroid. Tacrolimus is commenced 1 day before the liver transplant at a dosage of 0.1 mg/kg/d in 2 divided dosages and it is continued at the same dosage to attain therapeutic drug levels of 10 to 15 ng/ml for the first 3 months after liver transplant, and 5 to 10 ng/ml thereafter. Prednisolone is commenced immediately after liver transplant at a dosage of 1.5 mg/kg/d. The dosage is tapered to 10 mg/day until postoperative day 10, and the maintenance dosage is given 5 or 10 mg daily for 3 months in all transplant recipients except those with a liver disease of autoimmune hepatitis. Acute cellular rejections were initially suspected by biochemical evidence of deteriorating liver functions and clinical findings. After vascular or biliary complications were excluded by ultrasonography and computed tomography, liver biopsy was done to obtain certain pathologic evidence of rejection. The diagnosis of acute cellular rejections was based on internationally accepted histologic criteria (Banff guidelines) (4, 5). Our primary treatment for acute cellular rejections was to administer high-dose steroid (10 mg/kg/d) for 3 days, in conjunction with optimization of serum tacrolimus level between 8 to 12 ng/ml. Acute cellular rejections were defined as being steroid-resistant acute rejection, if no biochemical and clinical response to these therapies were observed, and additionally repeated acute rejection episodes within the first month after the steroid therapy was also defined as steroid-resistant acute rejection. After suspicion of steroid-resistant acute rejection, liver biopsy was repeated to obtain exact diagnosis. After confirming steroid-resistant acute rejection by biopsy, patients received 5 mg/kg/day antithymocyte globulin. The duration of antithymocyte globulin treatment was decided according to biochemical and clinical response of the patients. Patients received steroids (methyl prednisolone 100 mg for the first 3 days, then 40 mg, thereafter), an antihistamine (chlorphenoxamine hydrochloride 10 mg) and antipyretic (methimazole 100 mg) 2 hours before antithymocyte globulin infusion to reduce or prevent adverse effects of antithymocyte globulin. Additionally, calcineurin inhibitors were stopped and 5 mg/kg/day ganciclovir prophylaxis was given during antithymocyte globulin therapy. The third biopsy was not done when the improvements were achieved both in biochemical values and clinical status of the patients after steroidresistant acute-rejection treatment. Results There were 5 female, and 7 male patients with the mean age of ± 12.1 years (range, 5 to 40 years). Eight patients were children, and the remaining 4 patients were adult. The predominant cause of liver disease before liver transplant was fulminant hepatic failure in 5 patients (41.6%) who had steroid-resistant acute rejection. The cause of fulminant hepatic failure was acute hepatitis-a virus infection in 2 patients, acute non-a non-e hepatitis in 2 patients, and acute autoimmune hepatitis in 1 patient. The other remarkable causes of liver disease before transplant were Wilson disease in 3 patients (25%), cholestatic

3 174 Cem Aydogan et al / Experimental and Clinical Transplantation (2010) 2: Exp Clin Transplant Table 1. Characteristics of patients and liver biopsies. Case Sex Age (y) Donor Cause PELD/MELD Time of acute 1st Bx RAI Time of 2nd Bx RAI cellular rejection steroid-resistant (d) acute rejection (d) 1 M 10 LR WD M 6 C WD M 6 LR FHF (HAV) M 6 LR FHF (NANE) M 23 C HBV F 5 LR FHF (NANE) F 30 C FHF (Autoimmune) M 32 LR PSC M 14 LR WD F 8 LR CD F 13 LR FHF (HAV) F 40 C PSC Abbreviations: 1st Bx, the biopsy that the acute rejections were diagnosed; 2nd Bx, the biopsy that the steroid-resistant acute rejections were diagnosed; C, deceased; CD, Carolli disease; F, female; FHF, fulminant hepatic failure; HAV, hepatitis A virus; HBV, hepatitis B virus; LR, living related; M, male; MELD, model for end-stage liver disease; NANE, Non A Non E; PELD, pediatric end-stage liver disease score; PSC, primary sclerosing cholangitis; RAI, rejection activity index; WD, Wilson disease. liver disease in 3 patients (25%), and hepatitis B virus infection in 1 patient (Table 1). Grafts were obtained from a living-related donor in 8 patients (66.6%), and from a deceased donor in the remaining 4 patients. Most of the living-related donors were patients parents (58.3%), and all grafts were ABO compatible. The mean elapsed time from liver transplant to development of acute cellular rejection was ± days (range, days). Rejection activity index in the first liver biopsy that the acute cellular rejection was diagnosed was 7 in 5 patients, 5 in 5 patients, 6 in 1 patient, and 3 in 1 patient (Table 1). High-dose steroids (10 mg/kg/d) were administered to all these patients but these patients did not respond clinically and biochemically. A second biopsy was performed, and the diagnosis of steroid-resistant acute rejection was confirmed by this biopsy. The mean elapsed time from liver transplant to development of steroid-resistant acute rejection was ± days (range, days). Rejection activity index in the second biopsy was seven in 3 patients, four in 3 patients, three in 3 patients, five in 1 patient, six in 1 patient, and eight in the remaining 1 patient. When we compare the first and the second biopsy; rejection activity index decreased in 5 patients, increased in 3 patients, and did not change in remaining 4 patients. The characteristics of patients and liver biopsies were given in Table 1. The mean time of antithymocyte globulin treatment was ± 3.08 days (range, 5-14 days). Biochemical and clinical response to antithymocyte globulin treatment was achieved in 10 of these 12 patients (83.3%) who had steroid-resistant acute rejection. The Table 2. Mean biochemical values before and after the treatment of steroidresistant acute rejection. Before steroid-resistant acute rejection treatment After steroid-resistant acute rejection treatment Total bilirubin (mg/dl) ± ± 2.18 Direct bilirubin (mg/dl) 8.84 ± ± 1.98 Aspartate aminotransferase ± ± Alanine aminotransferase ± ± Alkaline phosphatase ± ± γ-glutamyl transpeptidase ± ± mean values of each liver function test improved (Table 2). The biochemical values returned to normal levels in 10 patients. We did not perform a third or control biopsy to these 10 patients. Although biochemical values decreased in remaining 2 patients (16.7%), they never reached acceptable values. Deterioration in their clinical status continued after antithymocyte globulin treatment and chronic rejection were detected in their third biopsies. They required retransplant at 7th and 8th month after their first liver transplant, which was done from livingrelated donors again; but both of them died due to sepsis on the 12th and 32nd day after retransplant. Liver functions of each patient before and after treatment of antithymocyte globulin are summarized in Table 3. The mean follow-up after steroid-resistant acute rejection treatment was 38.2 ± 26 months (range, 2-85 months). Fever and chills were the most commonly encountered adverse effects seen in 4 patients during antithymocyte globulin treatment.

4 Cem Aydogan et al / Experimental and Clinical Transplantation (2010) 2: Table 3. Liver function tests of each patient before and after the treatment of antithymocyte globulin. Case TB TB DB DB ALT ALT AST AST ALP ALP GGT γggt (pre) (post) (pre) (post) (pre) (post)(pre) (post) (pre) (post) (pre) (post) * * Abbreviations: ALP, alkaline phosphatase ; ALT, alanine aminotransferase ; AST, aspartate aminotransferase ; DB, direct bilirubin (mg/dl); GGT, γ-glutamyl transpeptidase ; TB, total bilirubin (mg/dl). *Patients who advanced chronic rejection. Table 4. Adverse effects and outcome of antithymocyte globulin treatment. Case Treatment Adverse effect of Posttreatment Current time (d) antithymocyte follow-up status globulin (mo) 1 10 Fever, anemia, headache 85 Alive 2 14 No 80 Alive 3 14 Fever, eruption, 2 Dead abdominal pain, nausea 4 10 Hypotension, anemia, 41 Alive leucopenia 5 10 Headache, hypotension 46 Alive 6 9 No 3 Dead 7 14 Fever, leucopenia 36 Alive 8 10 No 36 Alive 9 7 Fever, eruption, 35 Alive arthralgia, myalgia No 30 Alive Arthralgia, myalgia 27 Alive 12 5 No 25 Alive The other adverse effects that were observed during antithymocyte globulin treatment were eruption, arthralgia, myalgia, headache, dizziness, abdominal pain, nausea, hypotension, leucopenia, and anemia. We did not encounter any life-threatening or serious complications such as pulmonary edema, cytomegalovirus infections, or serious bacterial and fungal infections during antithymocyte globulin treatment and on follow-up. Adverse effects and outcome of antithymocyte globulin treatment are summarized in Table 4. Discussion Although effective immunosuppressive agents including calcineurin inhibitors, anti-interleukin-2 receptor antibodies, and mycophenolate mofetil are available, acute cellular rejections can be encountered in 36% to 57% of liver transplant recipients (2, 3, 6). Additionally, the rate of steroid resistant acute rejection was given between 28% and 35% (2, 6). The rate of acute cellular rejection, and steroid resistant acute rejection in our center were 30.5%, and 13.7%, respectively. Our rate of acute cellular rejections and steroid-resistant acute rejection are comparable with those series. Uemoto and colleagues (7) have emphasized the importance of refractory acute rejection and ductopenic rejection after living-donor liver transplant for fulminant hepatic failure in children. They reported that refractory acute rejection and ductopenic rejection occurred in 6 grafts each of children with non-a, non-b fulminant hepatic failure in a series of 19 children who underwent livingdonor liver transplant for fulminant hepatic failure. The investigators interpreted their results as a longlasting unknown viral infection that might have caused an accelerated immune response in children with non-a, non-b fulminant hepatic failure, and they intended to manage children with non-a, non- B fulminant hepatic failure by enhancing the immunosuppression protocol, including giving OKT3 as an initial treatment for rejection (7). Similarly, the predominant cause of liver disease before liver transplant in patients who had steroidresistant acute rejection was fulminant hepatic failure, which was seen in 5 patients (41.6%) in our series, and 4 of them were viral hepatitis. There are also reports that emphasize increased risk for acute cellular rejections and steroid-resistant acute rejection in liver diseases that have an autoimmune cause (8-10) and in other liver diseases, in which immune regulation is implicated, like primary sclerosing cholangitis (8). We observed 3 steroid-resistant acute rejection patients (25%) who had autoimmune causes of liver disease. Rescue therapy for steroid-resistant acute rejection includes antithymocyte globulin, monoclonal antibodies such as OKT3, mycophenolate mofetil, and anti-interleukin-2 receptor antibodies (daclizumab and basiliximab). The percentages of recovery in steroidresistant acute rejection treatment for mycophenolate mofetil and anti-interleukin 2 receptor antibodies had been reported 80.9% by Orr and colleagues and 75% by Pfitzmann and colleagues, (11, 12). Mycophenolate mofetil is well-known to cause gastrointestinal adverse effects in 24.6% to 52.5% of patients and bone marrow toxicity in 6.8% to 25.5%

5 176 Cem Aydogan et al / Experimental and Clinical Transplantation (2010) 2: Exp Clin Transplant of patients. Mycophenolate mofetil also has a risk of infection and malignancy in a dose-dependent manner (12, 13). The main advantage of mycophenolate mofetil as a rescue therapy is that it can be used continuously on an outpatient basis (12). However, this use of an agent requires patient adaptation and can be used only in selected patients. Anti-interleukin-2 receptor antibodies have been reported as effective and well-tolerated in steroidresistant acute rejection treatment. However, they need further study as first-line therapy for steroidresistant acute rejection (11). We prefer antithymocyte globulin in the treatment of steroid resistant acute rejection in our center. Ten of 12 patients (83.3%) who had steroid resistant acute rejections were treated successfully with antithymocyte globulin in our center. All alternatives have almost the same success. We believe that the transplant centers own experience in the treatment of steroid-resistant acute rejection is very important while managing this issue. Although therapeutic effects of antithymocyte globulin or murine monoclonal antibodies (OKT3) on rescue therapy of steroid-resistant acute rejection are well known, they have significant adverse effects (14). Early reactions include pyrexia, chills, and hypotension, secondary to cytokine release (15). Fever and chills were the most-commonly encountered adverse effects during antithymocyte globulin treatment in our study. The other adverse effects observed during antithymocyte globulin treatment were eruption, arthralgia, myalgia, headache, dizziness, abdominal pain, nausea, hypotension, leucopenia, and anemia. Similarly, adverse effects related to cytokine release and complaints like serum sickness were observed in our study group. All these adverse effects were seen on the first or second days of antithymocyte globulin treatment, and they were managed by close monitoring of the patients, appropriate interventions like fluid administration, antihistaminics, antipyretics, nonsteroidal antiinflammatory drugs, and prophylaxis. Anemia was treated with packages of red blood cells and leucopenia with GMCSF. There was no need to discontinue treatment in any patient owing to adverse effects during antithymocyte globulin treatment. Acceptable adverse effects were seen on the first or second days of antithymocyte globulin treatment and were managed by close monitoring of the patients and prophylaxis. In the longer term, adverse effects of antithymocyte globulin, including opportunistic infections, development of malignancy (16, 17), and recurrence of hepatitis C virus (18, 19) can be encountered when using these drugs. We did not encounter any malignancy and life-threatening opportunistic infection during the follow-up 38.2 ± 26 months (range, 2-85 months). More time is needed to draw any conclusions about malignancy development. Having no opportunistic infections can be attributed to infection prophylaxis in our study. In conclusion, according to our experiences, antithymocyte globulin can be a good therapeutic option in steroid-resistant acute rejection with acceptable adverse effects. The rate of steroid-resistant acute rejection is high after liver transplant in patients who have liver disease, owing to fulminant hepatic failure. References 1. Busuttil RW, Lake JR. Role of tacrolimus in the evolution of liver transplantation. Transplantation. 2004;77(suppl 9):S44-S Conti F, Dousset B, Archambeau D, Louvel A, Houssin D, Calmus Y. Enhanced risk of steroid-resistant acute rejection following pretransplant steroid therapy in liver graft recipients. 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