- Email: [email protected]
Sirolimus Monotherapy in Liver Transplantation
Sirolimus Monotherapy in Liver Transplantation F. Di Benedetto, S. Di Sandro, N. De Ruvo, M. Masetti, R. Montalti, A. Romano, G.P. Guerrini, R. Ballarin, M.G. De Blasiis, and G.E. Gerunda ABSTRACT Introduction. Since 1999, a new immunosuppressive drug was administered to renal transplant patients. The SRL molecule acts by blocking post-receptor signal transduction of interleukin-2 (IL-2) interacting with a family of intracellular binding proteins termed immunophilins FKBPs. Among these FKBPs, FK506 12-kd binding protein is the most relevant. SRL is an immunosuppressive drug. Therefore it can inhibit the immune system; at the same time the drug is not nephrotoxic, neurotoxic, and without diabetogenic effects. Methods. Among 285 patients who underwent liver transplantation, 27 took Sirolimus as monotherapy. Immunosuppressive treatment upto cyclosporine (CsA) or tacrolimus (FK) associated with steroids (methylprednisolone) and mycophenolate Mofetil (MMF) was initiated among subjects with pre-transplant renal failure. SRL was administered as monotherapy for patients who developed nephrotoxicity, or neurotoxicity, or diabetes. Moreover, patients affected by multifocal HCC who did not meet the Milan criteria or patients who developed Kaposi’s Sarcoma were prescribed SRL monotherapy. Results. Nephrotoxicity occurred in 14 patients with mean serum creatinine level 2.2 mg/dl. Eleven patients with real failure showed significant improvements after a mean period of 28 days of SRL monotherapy (range: 6 – 45 days). The mean creatinine serum level after treatment with SRL monotherapy was 1.0 mg/dl (range: 0.7–1.2 mg/dl). Neurotoxicity occurred in 4 patients with tremor, confusion, and agitation. Each patient had complete improvement of symptoms after a few days of Sirolimus monotherapy. Among Three patients who developed Kaposi’s Sarcoma, two underwent remission. One patient had diabetes due to calcineurin inhibitors, and one showed arterial hypertension not treatable with drugs. After the switch, we treated these patients with medications. Another important indication was HCC not meeting the Milan criteria. Conclusion. SRL monotherapy may be used to manage complication of calcineurin inhibitors or Kaposi’s Sarcoma.
S
INCE 1999, a new immunosuppressive drug was administered to renal transplant patients, after approval from Food and Drug Administration (FDA).1 This drug was derived from the mycelia of Streptomyces hygroscopicus showing antifungal properties particularly anticandidae. Consequently, several studies have revealed an important peculiarity of this drug – Sirolimus (SRL). It acts by blocking the post-receptor signal transduction of interleukin-2 (IL-2) interacting with a family of intracellular binding proteins termed immunophilins FKBPs, particularly the 12-kd binding protein. IL-2 is an important growth-factor for the cell, therefore SRL arrests the cell-cycle at the G1 to S phase,2–5 whereas, calcineurin
inhibitors (CNI) interfere with IL-2 gene transcription.3,4,5 CNIs have improved patient and graft survivals among transplant recipients, but showed significant complications: nephrotoxicity, neurotoxicity, hypertension, and diabetes mellitus. Usually, the management of CNI complications is From the Liver and Multivisceral Transplant Center, University of Modena and Reggio Emilia, Modena, Italy. Address correspondence to Fabrizio Di Benedetto, PhD, MD, Liver and Multivisceral Transplant Center, University of Modena and Reggio Emilia, Via del Pozzo, 71-41100 Modena, Italy. E-mail: [email protected]
0041-1345/07/$–see front matter doi:10.1016/j.transproceed.2007.07.018
© 2007 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
1930
Transplantation Proceedings, 39, 1930 –1932 (2007)
SIROLIMUS MONOTHERAPY
based on their doses reduction or possible suspension. This approach may improve or preserve renal function, but the patient is exposed to a major risk of graft rejection. SRL is an immunosuppressive drug that inhibits the immune system and at the same time is not nephrotoxic, neurotoxic, or diabetogenetic. However, SRL has numerous complications: leukopenia, thrombocytopenia, hypertriglyceridemia/ hypercholesterolemia, pulmonary disease, and joint pain. SRL requires control of drug levels because there is no immediate correspondence between dose and level.6,7 The aim of this study was to report our experience with 27 patients who underwent SRL monotherapy after a switch from CNIs. METHODS Among 285 patients who underwent orthotopic liver transplantation from October 2000 to November 2006, 27 recipients were switched to SRL monotherapy for various reasons. Immunosuppressive treatment included cyclosporine (CsA) or tacrolimus (FK) associated with steroids (methylprednisolone) administered with a bolus dose at liver reperfusion, and subsequent tapering doses over three months post-transplantation. Mofetil mycophenolate (MMF) was started in cases of pre-transplant or for patients developing acute or chronic renal failure after liver transplantation in association with lower doses of CNI. SRL was administered as monotherapy for patients who developed nephrotoxicity, neurotoxicity, or diabetes. Moreover, patients affected by multifocal HCC not meeting Milan criteria and patients who developed Kaposi’s Sarcoma were prescribed SRL monotherapy. To convert immunosuppressive therapy, we administered SRL the day after CNI suspension as a loading dose of 0.10 mg/kg on day 1. Subsequently, we administered 0.05 mg/kg daily for the next few days with dose adjustments seeking a trough level between 8 and 10 ng/mL. Pre-operative treatments were performed for Hepatocellular Carcinoma (HCC) and for severe portal venous hypertension. Hepatocellular carcinoma was treated with trans-arterial chemoembolization or with percutaneous thermoablation; while severe portal vein hypertension was treated by a transjugular Intrahepatic Portosystemic Shunt (TIPSS). During the waiting list time, all patients underwent hematochemical analyses, ␣-fetoprotein, hepatic ultrasound once per three months and a total body CT scan once per year. Rejection and HCV/HBV recurrences were treated if the liver biopsy proven consistent with the clinical suspicion. Rejection treatment consisted of steroids administered in the 1 g bolus with subsequent tapering. HCV recurrences were treated with ribavirin and peg-interferon for 6 months for HCV genotypes 2 or 3, and for 12 months for HCV genotypes 1 and 4. HBV prophylaxis consisted of lamivudine and scheduled anti-HbS IgG infusion (Hepatect).
RESULTS
The Recipient indications for liver transplantation were end-stage liver diseases caused by hepatic cirrhosis virusrelated (14 patients with HCV, 4 patients HBV, and 2 patients HBV-HCV). Three patients had a toxic cirrhosis, one had a diffuse angiomatosis, and one, hemochromatosis. Two patients developed HCC associated with a progressive story of alcohol. However, HCC occurred in eleven patients of this cohort in association with their basic disease. The mean age was 56 years (range: 33 to 65 years).
1931
CsA was administered in association with methylpredinisolone in 19 cases, while FK with methylpredinisolone in 8 cases. Steroids were tapered and stopped by the third month post-liver transplantation. Steroids were re-administered for three patients who developed acute cellular rejection. In a period ranging between 9 and 396 days, these patients were switched from CNI-based to SRL monotherapy. Nephrotoxicity had occurred in 14 patients with mean serum creatinine levels of 2.2 mg/dL. Eleven patients with renal failure showed significant improvement after a mean period of Sirolimus monotherapy of 28 days (range: 6 – 45 days). The mean serum creatinine level after treatment based on Sirolimus monotherapy was 1.0 mg/dL (range: 0.7–1.2 mg/dL). Three patients did not show significant improvement in serum creatinine level, however their serum creatinine level is 1.6 mg/dL. Neurotoxicity occurred in 4 patients: tremor, confusion, or agitation. Each patient displayed complete improvement in symptoms in a few days of Sirolimus monotherapy. Three patients developed Kaposi’s Sarcoma: two had cutaneous lesions, one had cutaneous and visceral lesions. Among these patients, two showed remission of Kaposi’s Sarcoma lesions; while one had significant improvement without complete remission. One patient was switched to Sirolimus monotheray because of diabetes due to CNI. His diabetes was initially refractory to insulin therapy, but after the switch it was controllable. One patient developed arterial hypertension not treatable with drugs. After the switch, we could be treated with anti-hypertensive medications. Another important indication to switch immunosuppressive therapy to Sirolimus monotherapy was HCC which did not meet Milan criteria. Three patients were switched to avoid HCC recurrence. Until now, HCC recurrence has not occurred after a mean period of one year of Sirolimus monotherapy. However, Sirolimus caused various complications. The most significant complication was leukopenia which occurred in 4 patients (14.8%). We suspended Sirolimus administration for three of these patients after 4, 5, 8 months, and restarted calcineurin inhibitors with leukopenia remission. The other two patients suspended Sirolimus monotherapy because of graft rejection. The most common complication was hypertriglyceridemia and hypercholesterolemia in 6 cases among 27 (22.2%). Three patients (11.1%) had graft rejection and four patients (14.8%). HCV recurrence during Sirolimus monotherapy. Two patients among twenty seven (7.4%) expired: one because of systemic aspergillosis, and another because of HCV recurrence. DISCUSSION
This study reports different indications to switch immunosuppressant from CIs to SRL monotherapy. CsA and FK have sensibly improved patient and graft survivale after liver transplantation. In spite of these advances, CIs are related to a multitude of side effects, often with significant compromise patient outcome. The principal CI complica-
1932
tions are nephotoxicity, neurotoxicity, diabetes, and arterial hypertension.8,9,10 Since few years, a new immunosuppressive drug is administered in patients with CI complication, and particularly in patients with renal failure CI-induced. SRL is not nephrotoxic drug, therefore its use is useful to keep to hold the patient under immunosuppressive therapy, and at the same time to avoid nephrotoxicity or others CI complications. SRL may be introduced in immunosuppressant therapy through two different methods.11 The first method consists in the introduction of SRL with low dose and contemporaneous decrement of CIs dose. Thus, this method not allows SRL administration as monotherapy. The second method allows the use of SRL as monotherapy. The first dose is a loading dose of 0.10 mg/kg, and consequent decrement of SRL to 0.05 mg/kg daily for the next few days were administered, with dose adjustments until a trough level between 8 and 10 ng/mL was achieved. This method is less used because of the higher risk of SRL side effects. Thus, SRL monotherapy allows higher dose of SRL, and subsequent higher serum level of this medication. Among our cohort of patients, we opted to use the second method of SRL administration for each patient. In our experience, indications to switch immunosuppressive therapy were not only related to CI complications, such as nephrotoxicity (51.8%), neurotoxicity (14.8%), diabetes (3.7%) and arterial hypertension (3.7%), but we also changed CI therapy due to Kaposi’s Sarcoma (11.1%) and HCC out of Milan criteria (11.1%). SRL monotherapy appeared effective in each case. Complete remission of complications occurred for 11 patients of 14 with nephrotoxicity, for all patients with neurotoxicity, and for 2 patients of 3 with Kaposi’s Sarcoma. Partial regression of symptoms occurred for remaining patients. Moreover, patients showed HCCs not meeting Milan criteria, did not show HCC recurrence until now. Different complications SRL-related occurred. In few cases we needed to suspend SRL therapy. In conclusion, SRL monotherapy may be considered an effective treatment method to manage CIs complication or Kaposi’s Sarcoma. Probably, we need to consider the opportunity to
DI BENEDETTO, DI SANDRO, DE RUVO ET AL
admin SRL monotherapy as first immunosuppression postliver transplantation among a selected cohort of recipients. Patients with advanced HCC may draw benefits from SRL because of antiproliferative effects expressed from SRL to avoid HCC recurrence. An other opportunity to use SRL monotherapy as prophylaxis treatment may regard patients HHV8 positive pre-transplantation. These patients have a significant risk to develop Kaposi’s Sarcoma, therefore SRL monotherapy could be indicated seen its proven effective on Kaposi’s Sarcoma. Furthermore, SRL monotherapy may be administered in patients underwent liver transplantation with known renal failure. REFERENCES 1. Watson CJ, Friend PJ, Jamieson NV, et al: Sirolimus: a potent new immunosuppressant for liver transplantation. Transplantation 67:505, 1999 2. Flanagan WM, Crabtree GR: Rapamycin inhibits p34cdc2 expression and arrests T lymphocyte proliferation at the G1/S transition. Ann N Y Acad Sci 696:31, 1993 3. Thomson AW, Woo J: Immunosuppressive properties of FK-506 and rapamycin. Lancet 2:443, 1989 4. Dumont FJ, Melino MR, Staruch MJ, et al: The immunosuppressive macrolides FK-506 and rapamycin act as reciprocal antagonists in murine T cells. J Immunol 144:1418, 1990 5. Dumont FJ, Staruch MJ, Koprak SL, et al: Distinct mechanisms of suppression of murine T cell activation by the related macrolides FK-506 and rapamycin. J Immunol 144:251, 1990 6. Flechner SM, Goldfarb D, Modlin C, et al: Kidney transplantation without calcineurin inhibitor drugs: a prospective, randomized trial of sirolimus versus cyclosporine. Transplantation 74:1070, 2002 7. Sehgal SN: Sirolimus: its discovery, biological properties, and mechanism of action. Transplant Proc 35(3 Suppl):7S, 2003 8. Platz KP, Mueller AR, Blumhardt G, et al: Nephrotoxicity after orthotopic liver transplantation in cyclosporin A and FK 506-treated patients. Transpl Int 7(Suppl 1):S52, 1994 9. Rimola A, Gavaler JS, Schade RR, et al: Effects of renal impairment on liver transplantation. Gastroenterol 93:148, 1987 10. Monsour HP Jr, Wood RP, Dyer CH, et al: Renal insufficiency and hypertension as long-term complications in liver transplantation. Semin Liver Dis 15:123, 1995 11. Maheshwari A, Torbenson MS, Thuluvath PJ: Sirolimus Monotherapy Versus Sirolimus in Combination with Steroids and/or MMF for Immunosuppression After Liver Transplantation. Dig Dis Sci. 2006 Sep 9.
S
INCE 1999, a new immunosuppressive drug was administered to renal transplant patients, after approval from Food and Drug Administration (FDA).1 This drug was derived from the mycelia of Streptomyces hygroscopicus showing antifungal properties particularly anticandidae. Consequently, several studies have revealed an important peculiarity of this drug – Sirolimus (SRL). It acts by blocking the post-receptor signal transduction of interleukin-2 (IL-2) interacting with a family of intracellular binding proteins termed immunophilins FKBPs, particularly the 12-kd binding protein. IL-2 is an important growth-factor for the cell, therefore SRL arrests the cell-cycle at the G1 to S phase,2–5 whereas, calcineurin
inhibitors (CNI) interfere with IL-2 gene transcription.3,4,5 CNIs have improved patient and graft survivals among transplant recipients, but showed significant complications: nephrotoxicity, neurotoxicity, hypertension, and diabetes mellitus. Usually, the management of CNI complications is From the Liver and Multivisceral Transplant Center, University of Modena and Reggio Emilia, Modena, Italy. Address correspondence to Fabrizio Di Benedetto, PhD, MD, Liver and Multivisceral Transplant Center, University of Modena and Reggio Emilia, Via del Pozzo, 71-41100 Modena, Italy. E-mail: [email protected]
0041-1345/07/$–see front matter doi:10.1016/j.transproceed.2007.07.018
© 2007 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
1930
Transplantation Proceedings, 39, 1930 –1932 (2007)
SIROLIMUS MONOTHERAPY
based on their doses reduction or possible suspension. This approach may improve or preserve renal function, but the patient is exposed to a major risk of graft rejection. SRL is an immunosuppressive drug that inhibits the immune system and at the same time is not nephrotoxic, neurotoxic, or diabetogenetic. However, SRL has numerous complications: leukopenia, thrombocytopenia, hypertriglyceridemia/ hypercholesterolemia, pulmonary disease, and joint pain. SRL requires control of drug levels because there is no immediate correspondence between dose and level.6,7 The aim of this study was to report our experience with 27 patients who underwent SRL monotherapy after a switch from CNIs. METHODS Among 285 patients who underwent orthotopic liver transplantation from October 2000 to November 2006, 27 recipients were switched to SRL monotherapy for various reasons. Immunosuppressive treatment included cyclosporine (CsA) or tacrolimus (FK) associated with steroids (methylprednisolone) administered with a bolus dose at liver reperfusion, and subsequent tapering doses over three months post-transplantation. Mofetil mycophenolate (MMF) was started in cases of pre-transplant or for patients developing acute or chronic renal failure after liver transplantation in association with lower doses of CNI. SRL was administered as monotherapy for patients who developed nephrotoxicity, neurotoxicity, or diabetes. Moreover, patients affected by multifocal HCC not meeting Milan criteria and patients who developed Kaposi’s Sarcoma were prescribed SRL monotherapy. To convert immunosuppressive therapy, we administered SRL the day after CNI suspension as a loading dose of 0.10 mg/kg on day 1. Subsequently, we administered 0.05 mg/kg daily for the next few days with dose adjustments seeking a trough level between 8 and 10 ng/mL. Pre-operative treatments were performed for Hepatocellular Carcinoma (HCC) and for severe portal venous hypertension. Hepatocellular carcinoma was treated with trans-arterial chemoembolization or with percutaneous thermoablation; while severe portal vein hypertension was treated by a transjugular Intrahepatic Portosystemic Shunt (TIPSS). During the waiting list time, all patients underwent hematochemical analyses, ␣-fetoprotein, hepatic ultrasound once per three months and a total body CT scan once per year. Rejection and HCV/HBV recurrences were treated if the liver biopsy proven consistent with the clinical suspicion. Rejection treatment consisted of steroids administered in the 1 g bolus with subsequent tapering. HCV recurrences were treated with ribavirin and peg-interferon for 6 months for HCV genotypes 2 or 3, and for 12 months for HCV genotypes 1 and 4. HBV prophylaxis consisted of lamivudine and scheduled anti-HbS IgG infusion (Hepatect).
RESULTS
The Recipient indications for liver transplantation were end-stage liver diseases caused by hepatic cirrhosis virusrelated (14 patients with HCV, 4 patients HBV, and 2 patients HBV-HCV). Three patients had a toxic cirrhosis, one had a diffuse angiomatosis, and one, hemochromatosis. Two patients developed HCC associated with a progressive story of alcohol. However, HCC occurred in eleven patients of this cohort in association with their basic disease. The mean age was 56 years (range: 33 to 65 years).
1931
CsA was administered in association with methylpredinisolone in 19 cases, while FK with methylpredinisolone in 8 cases. Steroids were tapered and stopped by the third month post-liver transplantation. Steroids were re-administered for three patients who developed acute cellular rejection. In a period ranging between 9 and 396 days, these patients were switched from CNI-based to SRL monotherapy. Nephrotoxicity had occurred in 14 patients with mean serum creatinine levels of 2.2 mg/dL. Eleven patients with renal failure showed significant improvement after a mean period of Sirolimus monotherapy of 28 days (range: 6 – 45 days). The mean serum creatinine level after treatment based on Sirolimus monotherapy was 1.0 mg/dL (range: 0.7–1.2 mg/dL). Three patients did not show significant improvement in serum creatinine level, however their serum creatinine level is 1.6 mg/dL. Neurotoxicity occurred in 4 patients: tremor, confusion, or agitation. Each patient displayed complete improvement in symptoms in a few days of Sirolimus monotherapy. Three patients developed Kaposi’s Sarcoma: two had cutaneous lesions, one had cutaneous and visceral lesions. Among these patients, two showed remission of Kaposi’s Sarcoma lesions; while one had significant improvement without complete remission. One patient was switched to Sirolimus monotheray because of diabetes due to CNI. His diabetes was initially refractory to insulin therapy, but after the switch it was controllable. One patient developed arterial hypertension not treatable with drugs. After the switch, we could be treated with anti-hypertensive medications. Another important indication to switch immunosuppressive therapy to Sirolimus monotherapy was HCC which did not meet Milan criteria. Three patients were switched to avoid HCC recurrence. Until now, HCC recurrence has not occurred after a mean period of one year of Sirolimus monotherapy. However, Sirolimus caused various complications. The most significant complication was leukopenia which occurred in 4 patients (14.8%). We suspended Sirolimus administration for three of these patients after 4, 5, 8 months, and restarted calcineurin inhibitors with leukopenia remission. The other two patients suspended Sirolimus monotherapy because of graft rejection. The most common complication was hypertriglyceridemia and hypercholesterolemia in 6 cases among 27 (22.2%). Three patients (11.1%) had graft rejection and four patients (14.8%). HCV recurrence during Sirolimus monotherapy. Two patients among twenty seven (7.4%) expired: one because of systemic aspergillosis, and another because of HCV recurrence. DISCUSSION
This study reports different indications to switch immunosuppressant from CIs to SRL monotherapy. CsA and FK have sensibly improved patient and graft survivale after liver transplantation. In spite of these advances, CIs are related to a multitude of side effects, often with significant compromise patient outcome. The principal CI complica-
1932
tions are nephotoxicity, neurotoxicity, diabetes, and arterial hypertension.8,9,10 Since few years, a new immunosuppressive drug is administered in patients with CI complication, and particularly in patients with renal failure CI-induced. SRL is not nephrotoxic drug, therefore its use is useful to keep to hold the patient under immunosuppressive therapy, and at the same time to avoid nephrotoxicity or others CI complications. SRL may be introduced in immunosuppressant therapy through two different methods.11 The first method consists in the introduction of SRL with low dose and contemporaneous decrement of CIs dose. Thus, this method not allows SRL administration as monotherapy. The second method allows the use of SRL as monotherapy. The first dose is a loading dose of 0.10 mg/kg, and consequent decrement of SRL to 0.05 mg/kg daily for the next few days were administered, with dose adjustments until a trough level between 8 and 10 ng/mL was achieved. This method is less used because of the higher risk of SRL side effects. Thus, SRL monotherapy allows higher dose of SRL, and subsequent higher serum level of this medication. Among our cohort of patients, we opted to use the second method of SRL administration for each patient. In our experience, indications to switch immunosuppressive therapy were not only related to CI complications, such as nephrotoxicity (51.8%), neurotoxicity (14.8%), diabetes (3.7%) and arterial hypertension (3.7%), but we also changed CI therapy due to Kaposi’s Sarcoma (11.1%) and HCC out of Milan criteria (11.1%). SRL monotherapy appeared effective in each case. Complete remission of complications occurred for 11 patients of 14 with nephrotoxicity, for all patients with neurotoxicity, and for 2 patients of 3 with Kaposi’s Sarcoma. Partial regression of symptoms occurred for remaining patients. Moreover, patients showed HCCs not meeting Milan criteria, did not show HCC recurrence until now. Different complications SRL-related occurred. In few cases we needed to suspend SRL therapy. In conclusion, SRL monotherapy may be considered an effective treatment method to manage CIs complication or Kaposi’s Sarcoma. Probably, we need to consider the opportunity to
DI BENEDETTO, DI SANDRO, DE RUVO ET AL
admin SRL monotherapy as first immunosuppression postliver transplantation among a selected cohort of recipients. Patients with advanced HCC may draw benefits from SRL because of antiproliferative effects expressed from SRL to avoid HCC recurrence. An other opportunity to use SRL monotherapy as prophylaxis treatment may regard patients HHV8 positive pre-transplantation. These patients have a significant risk to develop Kaposi’s Sarcoma, therefore SRL monotherapy could be indicated seen its proven effective on Kaposi’s Sarcoma. Furthermore, SRL monotherapy may be administered in patients underwent liver transplantation with known renal failure. REFERENCES 1. Watson CJ, Friend PJ, Jamieson NV, et al: Sirolimus: a potent new immunosuppressant for liver transplantation. Transplantation 67:505, 1999 2. Flanagan WM, Crabtree GR: Rapamycin inhibits p34cdc2 expression and arrests T lymphocyte proliferation at the G1/S transition. Ann N Y Acad Sci 696:31, 1993 3. Thomson AW, Woo J: Immunosuppressive properties of FK-506 and rapamycin. Lancet 2:443, 1989 4. Dumont FJ, Melino MR, Staruch MJ, et al: The immunosuppressive macrolides FK-506 and rapamycin act as reciprocal antagonists in murine T cells. J Immunol 144:1418, 1990 5. Dumont FJ, Staruch MJ, Koprak SL, et al: Distinct mechanisms of suppression of murine T cell activation by the related macrolides FK-506 and rapamycin. J Immunol 144:251, 1990 6. Flechner SM, Goldfarb D, Modlin C, et al: Kidney transplantation without calcineurin inhibitor drugs: a prospective, randomized trial of sirolimus versus cyclosporine. Transplantation 74:1070, 2002 7. Sehgal SN: Sirolimus: its discovery, biological properties, and mechanism of action. Transplant Proc 35(3 Suppl):7S, 2003 8. Platz KP, Mueller AR, Blumhardt G, et al: Nephrotoxicity after orthotopic liver transplantation in cyclosporin A and FK 506-treated patients. Transpl Int 7(Suppl 1):S52, 1994 9. Rimola A, Gavaler JS, Schade RR, et al: Effects of renal impairment on liver transplantation. Gastroenterol 93:148, 1987 10. Monsour HP Jr, Wood RP, Dyer CH, et al: Renal insufficiency and hypertension as long-term complications in liver transplantation. Semin Liver Dis 15:123, 1995 11. Maheshwari A, Torbenson MS, Thuluvath PJ: Sirolimus Monotherapy Versus Sirolimus in Combination with Steroids and/or MMF for Immunosuppression After Liver Transplantation. Dig Dis Sci. 2006 Sep 9.