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A Safe Immunosuppressive Protocol in Adult-to-Adult Living Related Liver Transplantation

A Safe Immunosuppressive Protocol in Adult-to-Adult Living Related Liver Transplantation
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   A Safe Immunosuppressive Protocol in Adult-to-Adult LivingRelated Liver Transplantation S. Gruttadauria, D. Cintorino, T. Piazza, L. Mandala, E. Doffria, A. Musumeci, G. Di Trapani, A. Arcadipane, G. Scianna, M. Spada, R. Verzaro, R. Volpes, G. Vizzini, U. Palazzo, M. Minervini,J.W. Marsh, A. Marcos, and B. Gridelli ABSTRACTBackground.  In this series of 32 adult-to-adult living related liver transplantations, weassessed the efficacy and safety of basiliximab in combination with a tacrolimus-basedregimen. Basiliximab, a chimeric monoclonal antibody directed against the alpha chain of the interleukin-2 (IL-2) receptor (CD25), has been extensively evaluated as inductiontherapy for cadaveric liver transplant recipients. Patients and Methods.  Thirty-two adult-to-adult living related liver transplantations were performed in the last 3 years. All patients received two 20 mg doses of basiliximab(days 0 and 4 posttransplantation) followed by tacrolimus (0.15 mg/kg/d; 10–15 ng/mL target trough levels) and steroids (starting with 20 mg IV switched to PO as soon as thepatient was able to eat and weaned within 1–2 months). The average follow-up was 395days after transplantation. Results.  Of the patients, 93.75% remained rejection-free during follow-up with anactuarial rejection-free probability of 92.59% within 3 months. Two patients (6%) had oneepisode of biopsy-proven acute cellular rejection (ACR). Actuarial patient and graftsurvival rates at 3 years were 86.85% and 81.25%. One patient (3%) experienced oneepisode of sepsis. There was no evidence of cytomegalovirus infections or side effectsrelated to the basiliximab. We found zero de novo malignancy but we observed twopatients with metastatic spread of their primary malignancy during the follow-up. Conclusion.  Basiliximab in association with tacrolimus and steroids is effective asprophylaxis of ACR among adult living related liver transplant recipients. D ESPITE ADVANCES in patient selection, surgicaltechnique, immunosuppression, and perioperativemanagement, the need for liver transplantation exceedsorgan availability. This persistent ongoing shortage of or-gans has led surgeons to develop innovative techniques toexpand the donor pool, namely, living donor liver transplan-tation, which represents the natural evolution of the proce-dure based on the segmental anatomy of the liver as thereduced size cadaveric and split liver transplants. 1 Livingrelated liver transplantation has now become the standardtreatment for many end-stage liver diseases in the adultpopulation. 2 This has led transplant surgeons involved inadult-to-adult living related liver transplantation (ALRLT)to put more emphasis on the evaluation of new immuno-suppressive protocols considering the particular conditionpresented by these living recipients and aiming to achievefewer drug side effects and toxicity while looking at poten-tial induction of tolerance. 3 The transplanted liver is generally considered immuno-logically privileged, regardless of whether the source of donation is living or cadaveric, with low incidences of graftloss related to acute or chronic rejection. However, despite From the Istituto Mediterraneo Trapianti e Terapie ad AttaSpecializzazione (IsMeTT) (S.G., D.C., T.P., L.M., E.D., A.M.,G.D., A.A., G.S., M.S., R.V., R.Vo., G.V., V.P., M.M., B.G.),University of Pittsburgh Medical Center (UPMC) (S.G., M.S.,J.W.M., A.M., B.G.) Italy, Palermo, Italy, and the UMPC, Pitts-burgh, Pennsylvania, USA. Address reprint requests to Salvatore Gruttadauria, MD, IsMeTTUPMC Italy, Via E. Tricomi N. 1, 90127 Palermo, Italy. E-mail:sgruttadauria@ismett.edu0041-1345/06/$–see front matter © 2006 by Elsevier Inc. All rights reserved.doi:10.1016/j.transproceed.2006.02.141 360 Park Avenue South, New York, NY 10010-17101106  Transplantation Proceedings,  38, 1106–1108 (2006)  advances in immunosuppression, acute cellular rejection(ACR) remains an important risk factor. Antibody induc-tion is a means of reducing the risk of ACR in the earlyposttransplantation period, while simultaneously attempt-ing to avoid the long-term use of corticosteroids. Herein wereport our experience with a retrospective analysis on agroup of adult recipients who received a liver transplantfrom a living donor, aiming to reduce the risk of rejectionand to obtain early weaning from steroids. The immuno-suppressive protocol was based on our previous experience with patients who received cadaveric liver donations, 4 thusthis series represents a learning curve reflecting surgical andclinical management improvements. PATIENTS AND METHODS Our series included 32 consecutive adult patients (ages 18–68 years) suffering from end-stage liver cirrhosis secondary to viraletiology (10 patients), hepatocellular carcinoma on viral cirrhosisin 16 cases (incidentally in 1 of these cases an additional intrahe-patic cholangiocarcinoma was diagnosed), cystic fibrosis in 2 cases,primary biliary cirrhosis in 2 cases, hepatocellular carcinoma onalcohol-related cirrhosis in 1 case, and metastatic carcinoid to theliver in 1 case. The donors (ages 18–53 years) all had genetic oremotional relationships with the recipients; 25 couples were ABOidentical and 7 compatible.Donor liver resections resulted in 30 right hepatectomies and 2 lefthepatectomies; graft implantation was performed with the preserva-tion of the recipient inferior vena cava, and in 26 cases with the use of  veno-venous bypass. Donor evaluation, surgical technique, and pro-tocol management have been previously described. 5 The immunosuppression included 20 mg basiliximab (Simulect),an interleukin-2 (IL-2) chimeric receptor antibody 6–8 directedagainst the alpha chain (CD25), which is expressed on activated Tcells. As inhibitors of IL-2 binding, they prevent ACR byinhibiting IL-2-driven T-cell proliferation. This was given inassociation with 500 mg to 1 g methylprednisolone at the time of liver reperfusion; both were given by IV bolus. An additional20 mg dose of basiliximab was administered by IV bolus on day4 after transplantation. Tacrolimus (Prograf) was administered at0.15 mg/kg/d by mouth or through the nasogastric tube starting within 24 hours after the ALRLT, and adjusted to achieve troughlevels in the range of 8 to 10 ng/mL. At 30 days posttransplantation,the target trough level was reduced to 5 to 7 ng/mL. Corticosteroids were administered in a standard rapid taper regimen for the firstmonth of methylprednisolone at 50 mg IV every 6 hours on day 1;40 mg IV every 6 hours on day 2; 30 mg IV every 6 hours on day3; 20 mg IV every 6 hours on day 4; and 20 mg IV every 12 hourson day 5; and 20 mg prednisone by mouth or through thenasogastric tube on days 6 to 15; then 10 mg/d for 1 week; and5 mg/d for 1 additional week. After the first year, we just prescribed methylprednisone 20 mgIV for the first 2 to 3 days and then 20 mg prednisone by mouth,slowly decreasing and weaning from corticosteroid within 1 to 2months. In the case of ACR, depending on the gravity of therejection, the protocol comprised a bolus administration of 500 mgmethylprednisolone to be repeated 3 times. Simultaneously, thetacrolimus target level was increased to 8 to 10 ng/mL.Cytomegalovirus (CMV) pp65 antigenemia-guided preemptivetherapy was used for CMV prophylaxis; surveillance for CMV anti-genemia was performed at weeks 2, 4, 6, 8, 12, and 16 posttransplan-tation. If positive, oral ganciclovir was used for 6 weeks. 9 The average follow-up was 395 days after transplantation. Pa-rameters evaluated included graft failure, need and indication forretransplantation, and number of retransplantations. Patient survival/ death, ACR-free time, and infection rate also were measured. Thediagnosis of ACR was always biopsy proven. Statistical Analysis The Kaplan-Meier method was used to measure survival. Theanalyses were performed using SPSS (SPSS Inc, Chicago, Ill,United States). RESULTS The cohort included 17 men and 15 women. The mostcommon CMV status was donor positive/recipient positive;however, all combinations of CMV status were represented.The mean total ischemia time from the time of hepaticartery cross-clamping during the donor operation and theliver reperfusion was 137 minutes. Actuarial patient survival rate at 3 years was 86.85% andgraft survival rate was 81.25% (Fig 1). Graft loss occurred insix patients. Four patients underwent retransplantation: twocases due to hepatic artery thrombosis, one patient due tograft dysfunction, and one patient due to spontaneousrupture of hepatic artery anastomoses.There were four deaths, all due to sepsis. Of all patients,93.75% were free of ACR episodes during the follow-upperiod, with a rejection-free probability of 92.59% within 3months. Two patients (6%) had one ACR episode, both within 3 months (one mild and one moderate in severity);OKT3 or other antibody therapy was never required to treatrejection.Onepatient(3%)experiencedoneepisodeofsepsis,requir-ing temporary reduction of immunosuppressive therapy.There was no evidence of CMV infection. We found zero denovo malignancy but we observed one patient with pulmonaryrecurrence of his hepatocellular carcinoma and one patient with bone recurrence of her intrahepatic cholangiocarcinoma.Basiliximab was well tolerated by all patients. No acute sideeffects were noted, including any acute infusion reactions. Nopatients or grafts were lost due to acute or chronic rejection. DISCUSSION Corticosteroids have well-known side effects that result insignificant morbidities, including hypertension, obesity, diabe-tes, hyperlipidemia, and infectious complications. Previousreports have shown that early reduction or elimination of corticosteroids could significantly reduce the incidence of many complications in liver transplant recipients. Moreover,corticosteroids are frequently implicated in the acceleration of  viral replication and recurrence after liver transplantation. 10 With the advent of newer immunosuppressive agents, includ-ing tacrolimus, mycophenolate, IL-2 receptor antibody, andsirolimus, early steroid reduction or withdrawal in cadavericliver transplant recipients appears to be practical.This study showed that basiliximab in a tacrolimus-basedimmunosuppressive regimen is well tolerated and effective in IMMUNOSUPPRESSIVE PROTOCOL IN ALRLT 1107  both reducing episodes of ACR and increasing ACR-freesurvival after ALRLT. Our data support the use of basiliximabin ALRLT recipients treated with tacrolimus-based immuno-suppression as a strategy to decrease ACR while avoiding theserious adverse effects associated with broad T-cell depletion.However, monoclonal antibodies also may be beneficial topatients when used in calcineurin inhibitor–sparing regi-mens. In such regimens, monoclonal antibodies could facil-itate the early withdrawal of calcineurin inhibitors, thusreducing the risk for nephrotoxicity and neurotoxicity.In conclusion, this study demonstrated that basiliximab, achimeric monoclonal antibody directed against the IL-2 recep-tor (CD25), effectively reduced the number of ACR episodesand increased the probability of remaining rejection-free after ALRLT, which could potentially result in improved long-termoutcomes. In addition, the study showed that basiliximab wassafeanddidnotincreasetheadverseeventprofileorinfection.Investigation of the potential of this regimen to allow subse-quent weaning from maintenance immunosuppressants isneeded in larger groups of both cadaveric and living relatedliver transplant recipients especially in the era of potentialtolerance induction. REFERENCES 1. Heffron TG, Gruttadauria S, Campi O, et al: Surgical inno- vations in pediatric liver transplantation: reduced-size, split, andliving-related transplantation. Prob Gen Surg 15:104, 19982. Marcos A: Right lobe living donor liver transplantation: areview. Liver Transpl 6:3, 20003. Ringe B, Moritz M, Zeldin G, et al: What is the bestimmunosuppression in living donor liver transplantation? Trans-plant Proc 37:2169, 20054. Gruttadauria S, Vasta F, Mandala L, et al: Basiliximab in atriple-drug regimen with tacrolimus and steroids in liver transplan-tation. Transplant Proc 37:2611, 20055. Gruttadauria S, Mandala L, Cintorino D, et al: Improvementin hepatic parenchymal transection for living related liver donor.Transplant Proc 37:2589, 20056. Kahan BD, Rajagopalan PR, Hall M, et al: Reduction of theoccurrence of acute cellular rejection among renal allograft recip-ients treated with basiliximab, a chimeric anti-interleukin-2 recep-tor monoclonal antibody. Transplantation 67:276, 19997. Ponticelli C, Yussim A, Cambi V, et al: A randomized, double-blind trial of basiliximab immunoprophylaxis plus triple therapy inkidney transplant recipients. Transplantation 72:1261, 20018. Lawen JG, Davies EA, Mourad G, et al: Randomized double-blind study of immunoprophylaxis with basiliximab, a chimericanti-interleukin-2 receptor monoclonal antibody, in combination with mycophenolate mofetil-containing triple therapy in renaltransplantation. Transplantation 75:37, 20039. Singh N, Paterson DL, Gayowski T, et al: Cytomegalovirusantigenemia directed pre-emptive prophylaxis with oral versus I.V.ganciclovir for the prevention of cytomegalovirus disease in livertransplant recipients: a randomized, controlled trial. Transplanta-tion 70:717, 200010. Marino IR, Doria C, Scott VL, et al: Efficacy and safety of basiliximab with a tacrolimus-based regimen in liver transplantrecipients. Transplantation 78:886, 2004 Fig 1.  Three-year actuarial survival curve (Kaplan-Meier) after adult-to-adult living related liver transplantation.1108 GRUTTADAURIA, CINTORINO, PIAZZA ET AL
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