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1
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Gabrielli F, Bernasconi E, Toscano A, Avossa A, Cavicchioli A, Andreone P, Gitto S. Side Effects of Immunosuppressant Drugs After Liver Transplant. Pharmaceuticals (Basel) 2025; 18:342. [PMID: 40143120 PMCID: PMC11946649 DOI: 10.3390/ph18030342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2025] [Revised: 02/18/2025] [Accepted: 02/26/2025] [Indexed: 03/28/2025] Open
Abstract
Liver transplantation (LT) is the standard of care for both end-stage liver failure and hepatocellular carcinoma (HCC). Side effects of the main used immunosuppressive drugs have a noteworthy impact on the long-term outcome of LT recipients. Consequently, to achieve a balance between optimal immunosuppression and minimal side effects is a cornerstone of the post-LT period. Today, there are no validated markers for overimmunosuppression and underimmunosuppression, only a few drugs have therapeutic drug monitoring, and immunosuppression regimens vary from center to center and from country to country. Currently, there are many drugs with different efficacy and safety profiles. Using different agents permits a decrease in the dosage and minimizes the toxicities. A small subset of recipients achieves immunotolerance with the chance to stop immunosuppressive therapy. This article focuses on the side effects of immunosuppressive drugs, which significantly impact long-term outcomes for LT recipients. The primary aim is to highlight the balance between achieving effective immunosuppression and minimizing adverse effects, emphasizing the role of personalized therapeutic strategies. Moreover, this review evaluates the mechanisms of action and specific complications associated with immunosuppressive agents. Finally, special attention is given to strategies for reducing immunosuppressive burdens, improving patient quality of life, and identifying immunotolerant individuals.
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Affiliation(s)
- Filippo Gabrielli
- Internal and Metabolic Medicine, Department of Medical and Surgical Sciences for Children & Adults, AOU of Modena, University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Elisa Bernasconi
- Postgraduate School of Internal Medicine, University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Arianna Toscano
- Division of Internal Medicine, University Hospital of Policlinico G. Martino, 98124 Messina, Italy
| | - Alessandra Avossa
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy
| | - Alessia Cavicchioli
- Internal and Metabolic Medicine, Department of Medical and Surgical Sciences for Children & Adults, AOU of Modena, University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Pietro Andreone
- Internal and Metabolic Medicine, Department of Medical and Surgical Sciences for Children & Adults, AOU of Modena, University of Modena and Reggio Emilia, 41126 Modena, Italy
- Postgraduate School of Allergology and Clinical Immunology, University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Stefano Gitto
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy
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2
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Kalogirou MS, Giouleme O. Growing challenge of post-liver transplantation non-alcoholic fatty liver disease. World J Transplant 2022; 12:281-287. [PMID: 36187880 PMCID: PMC9516490 DOI: 10.5500/wjt.v12.i9.281] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 07/19/2022] [Accepted: 08/16/2022] [Indexed: 02/05/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is one of the leading causes of chronic liver disease, cirrhosis, and hepatocellular carcinoma worldwide, with an estimated prevalence of 25%. Post-liver transplantation (LT) recurrent or de novo hepatic steatosis is a common complication in recipients, irrespective of transplantation indication. Risk factors for graft steatosis mainly include obesity, immunosuppression, donor steatosis, and genetic factors. Liver transplant recipients are at high risk of developing insulin resistance, new-onset diabetes, and post-transplantation metabolic syndrome that is highly associated with immunosuppressive treatment. Post-LT NAFLD is often underdiagnosed due to the poor sensitivity of most routine imaging methods. The gold standard for the diagnosis of hepatic steatosis is liver biopsy, which is, however, limited to more complex cases due to its invasive nature. There is no approved pharmacotherapy in NAFLD. Lifestyle modification remains the cornerstone in NAFLD treatment. Other treatment strategies in post-LT NAFLD include lifestyle modifications, pharmacotherapy, bariatric surgery, and tailored immunosuppression. However, these approaches originate from recommendations in the general population, as there is scarce data regarding the safety and efficacy of current management strategies for NAFLD in liver transplant patients. Future prospective studies are required to achieve tailored treatment for these patients.
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Affiliation(s)
- Maria Styliani Kalogirou
- Gastroenterology and Hepatology Division of the Second Propedeutic Department of Internal Medicine, Hippokration General Hospital, Medical School, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
| | - Olga Giouleme
- Gastroenterology and Hepatology Division of the Second Propedeutic Department of Internal Medicine, Hippokration General Hospital, Medical School, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
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3
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Plaz MC, Tsochatzis EA. Metabolic Complications Before and After Liver Transplantation. TEXTBOOK OF LIVER TRANSPLANTATION 2022:357-371. [DOI: 10.1007/978-3-030-82930-8_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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4
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Sertić Z, Letilović T, Kanižaj TF, Knotek M, Hadžibegović I, Starovečki I, Jerkić H. Cardiovascular mortality in liver and kidney transplant recipients: A retrospective analysis from a single institution. Medicine (Baltimore) 2021; 100:e26019. [PMID: 34011105 PMCID: PMC8137067 DOI: 10.1097/md.0000000000026019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Accepted: 04/30/2021] [Indexed: 01/05/2023] Open
Abstract
Previous studies have demonstrated cardiovascular causes to be among the leading causes of death after liver (LT) and kidney transplantation (KT). Although both recipient populations have unique pre-transplant cardiovascular burdens, they share similarities in post-transplant exposure to cardiovascular risk factors. The aim of this study was to compare cardiovascular mortality after LT and KT.We analyzed causes of death in 370 consecutive LT and 207 KT recipients from in-hospital records at a single tertiary transplant center. Cardiovascular causes of death were defined as cardiac arrest, heart failure, pulmonary embolism, or myocardial infarction.After a median follow-up of 36.5 months, infection was the most common cause of death in both cohorts, followed by cardiovascular causes in KT recipients and graft-related causes in LT recipients in whom cardiovascular causes were the third most common. Cumulative incidence curves for cardiovascular mortality computed with death from other causes as the competing risk were not significantly different (P = .36). While 1-year cumulative cardiovascular mortality was similar (1.6% after LT and 1.5% after KT), the estimated 4-year probability was higher post-KT (3.8% vs. 1.6%). Significant pre-transplant risk factors for overall mortality after KT in multivariable analysis were age at transplantation, left ventricular ejection fraction <50%, and diastolic dysfunction grade 2 or greater, while significant risk factors for cardiovascular mortality were peripheral artery disease and left ventricular ejection fraction <50%. In the LT group no variables remained significant in a multivariable model for either overall or cardiovascular mortality.The present study found no significant overall difference in cardiovascular mortality after LT and KT. While LT and KT recipients may have similar early cardiovascular mortality, long-term risk is potentially lower after LT. Differing characteristics of cardiovascular death between these two patient populations should be further investigated.
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Affiliation(s)
- Zrinka Sertić
- Department of Emergency Medicine, University Hospital Centre Zagreb
| | - Tomislav Letilović
- Division of Cardiology, University Hospital Merkur
- School of Medicine, University of Zagreb
| | - Tajana Filipec Kanižaj
- School of Medicine, University of Zagreb
- Division of Gastroenterology, University Hospital Merkur, Zagreb, Croatia
| | | | - Irzal Hadžibegović
- Division of Cardiology, University Hospital Dubrava, Zagreb
- Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia
| | | | - Helena Jerkić
- Division of Cardiology, University Hospital Merkur
- School of Medicine, University of Zagreb
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5
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Burra P, Becchetti C, Germani G. NAFLD and liver transplantation: Disease burden, current management and future challenges. JHEP Rep 2020; 2:100192. [PMID: 33163950 PMCID: PMC7607500 DOI: 10.1016/j.jhepr.2020.100192] [Citation(s) in RCA: 125] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2020] [Revised: 08/06/2020] [Accepted: 08/13/2020] [Indexed: 02/07/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD), specifically its progressive form non-alcoholic steatohepatitis (NASH), represents the fastest growing indication for liver transplantation in Western countries. Diabetes mellitus, morbid obesity and cardiovascular disease are frequently present in patients with NAFLD who are candidates for liver transplantation. These factors require specific evaluation, including a detailed pre-surgical risk stratification, in order to improve outcomes after liver transplantation. Moreover, in the post-transplantation setting, the incidence of cardiovascular events and metabolic complications can be amplified by immunosuppressive therapy, which is a well-known driver of metabolic alterations. Indeed, patients with NASH are more prone to developing early post-transplant complications and, in the long-term, de novo malignancy and cardiovascular events, corresponding to higher mortality rates. Therefore, a tailored multidisciplinary approach is required for these patients, both before and after liver transplantation. Appropriate candidate selection, lifestyle modifications and specific assessment in the pre-transplant setting, as well as pharmacological strategies, adjustment of immunosuppression and a healthy lifestyle in the post-transplant setting, play a key role in correct management.
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Key Words
- CKD, chronic kidney disease
- CNI, calcineurin inhibitors
- DM, diabetes mellitus
- DPP-4, dipeptidyl peptidase-4
- ELTR, European Liver Transplant Registry
- ESLD, end-stage liver disease
- GLP1 RAs, glucagon-like peptide-1 receptor agonists
- Graft survival
- HCC, hepatocellular carcinoma
- HR, hazard ratio
- Hypertension
- IRR, incidence rate ratio
- Immunosuppressant
- LT, liver transplant
- MAFLD, metabolic dysfunction-associated fatty liver disease
- Metabolic complication
- NAFLD, non-alcoholic fatty liver disease
- NASH, non-alcoholic steatohepatitis
- New-onset diabetes after transplantation
- Non-alcoholic fatty liver disease
- Non-alcoholic steatohepatitis
- OR, odds ratio
- Obesity
- Patient survival
- SGLT2, sodium-glucose co-transporter-2
- Solid organ transplantation
- UNOS, United Network for Organ Sharing
- mTORi, mammalian target of rapamycin inhibitors
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Affiliation(s)
- Patrizia Burra
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, University Hospital Padua, University of Padua, Padua, Italy
- Corresponding author. Address: Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital. Tel.: +39 0498212892; fax: + 390498217848.
| | - Chiara Becchetti
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, University Hospital Padua, University of Padua, Padua, Italy
- Hepatology, Department of Visceral Surgery and Medicine, Inselspital, University Hospital Bern, Department of Biomedical Research, University of Bern, Bern, Switzerland
| | - Giacomo Germani
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, University Hospital Padua, University of Padua, Padua, Italy
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6
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Steggerda JA, Mahendraraj K, Todo T, Noureddin M. Clinical considerations in the management of non-alcoholic steatohepatitis cirrhosis pre- and post-transplant: A multi-system challenge. World J Gastroenterol 2020; 26:4018-4035. [PMID: 32821068 PMCID: PMC7403794 DOI: 10.3748/wjg.v26.i28.4018] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Revised: 05/07/2020] [Accepted: 07/14/2020] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic steatohepatitis (NASH) is the most common chronic liver disease worldwide, and the fastest growing indication for liver transplantation in the United States. NASH is now the leading etiology for liver transplantation in women, the second leading indication for men, and the most common cause amongst recipients aged 65 years and older. Patients with end-stage liver disease related to NASH represent a unique and challenging patient population due the high incidence of associated comorbid diseases, including obesity, type 2 diabetes (T2D), and hypertension. These challenges manifest in the pre-liver transplantation period with increased waitlist times and waitlist mortality. Furthermore, these patients carry considerable risk of morbidity and mortality both before after liver transplantation, with high rates of T2D, cardiovascular disease, chronic kidney disease, poor nutrition, and disease recurrence. Successful transplantation for these patients requires identification and management of their comorbidities in the face of liver failure. Multidisciplinary evaluations include a thorough pre-transplant workup with a complete cardiac evaluation, control of diabetes, nutritional support, and even, potentially, consultation with a bariatric surgeon. This article provides a comprehensive review of the conditions and challenges facing patients with NASH cirrhosis undergoing liver transplantation and provides recommendations for evaluation and management to optimize them before liver transplantation to produce successful outcomes.
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Affiliation(s)
- Justin A Steggerda
- Department of Surgery, Division of Transplantation, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
| | - Krishnaraj Mahendraraj
- Department of Surgery, Division of Transplantation, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
| | - Tsuyoshi Todo
- Department of Surgery, Division of Transplantation, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
| | - Mazen Noureddin
- Division of Digestive and Liver Diseases, Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
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7
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Becchetti C, Dirchwolf M, Banz V, Dufour JF. Medical management of metabolic and cardiovascular complications after liver transplantation. World J Gastroenterol 2020; 26:2138-2154. [PMID: 32476781 PMCID: PMC7235200 DOI: 10.3748/wjg.v26.i18.2138] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Revised: 03/26/2020] [Accepted: 04/28/2020] [Indexed: 02/06/2023] Open
Abstract
Liver transplantation represents the only curative option for patients with end-stage liver disease, fulminant hepatitis and advanced hepatocellular carcinoma. Even though major advances in transplantation in the last decades have achieved excellent survival rates in the early post-transplantation period, long-term survival is hampered by the lack of improvement in survival in the late post transplantation period (over 5 years after transplantation). The main etiologies for late mortality are malignancies and cardiovascular complications. The latter are increasingly prevalent in liver transplant recipients due to the development or worsening of metabolic syndrome and all its components (arterial hypertension, dyslipidemia, obesity, renal injury, etc.). These comorbidities result from a combination of pre-liver transplant features, immunosuppressive agent side-effects, changes in metabolism and hemodynamics after liver transplantation and the adoption of a sedentary lifestyle. In this review we describe the most prevalent metabolic and cardiovascular complications present after liver transplantation, as well as proposing management strategies.
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Affiliation(s)
- Chiara Becchetti
- Hepatology, Department of Visceral Surgery and Medicine, Inselspital, University Hospital Bern, Bern CH-3008, Switzerland
- Department of Biomedical Research, University of Bern, Bern CH-3008, Switzerland
| | - Melisa Dirchwolf
- Hepatology, Department of Visceral Surgery and Medicine, Inselspital, University Hospital Bern, Bern CH-3008, Switzerland
- Department of Biomedical Research, University of Bern, Bern CH-3008, Switzerland
- Hepatology, Hepatobiliary Surgery and Liver Transplant Unit, Hospital Privado de Rosario, Rosario S2000GAP, Santa Fe, Argentina
| | - Vanessa Banz
- Department of Visceral Surgery and Medicine, Inselspital, University Hospital Bern, Bern CH-3008, Switzerland
- Department of Clinical Research, University of Bern, Bern CH-3008, Switzerland
| | - Jean-François Dufour
- Hepatology, Department of Visceral Surgery and Medicine, Inselspital, University Hospital Bern, Bern CH-3008, Switzerland
- Department of Biomedical Research, University of Bern, Bern CH-3008, Switzerland
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8
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Warden BA, Duell PB. Management of dyslipidemia in adult solid organ transplant recipients. J Clin Lipidol 2019; 13:231-245. [PMID: 30928441 DOI: 10.1016/j.jacl.2019.01.011] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Revised: 01/21/2019] [Accepted: 01/22/2019] [Indexed: 02/07/2023]
Abstract
Solid organ transplantation (SOT) has revolutionized treatment of end-stage disease. Improvements in the SOT continuum of care have unmasked a significant burden of cardiovascular disease, manifesting as a leading cause of morbidity and mortality. Although several risk factors for development of post-transplant cardiovascular disease exist, dyslipidemia remains one of the most frequent and modifiable risks. An important contributor to dyslipidemia in SOT recipients is the off-target metabolic effects of immunosuppressive medications, which may alter lipoproteins and their metabolism. Dyslipidemia management is paramount as lipid-lowering therapy with statins has demonstrated reductions in graft vasculopathy, decreased rejection rates, and improved survival. Several nonstatin medication options are available, but data supporting their benefit in the SOT population are minimal, typically extrapolated from studies in the general population. Further compounding dyslipidemia management is the complex interplay of drug interactions between lipid-lowering and immunosuppressant medications, which can result in serious toxicity and/or therapeutic failure.
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Affiliation(s)
- Bruce A Warden
- Center for Preventive Cardiology, Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR, USA
| | - P Barton Duell
- Center for Preventive Cardiology, Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR, USA.
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9
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Khurmi NS, Chang YH, Eric Steidley D, Singer AL, Hewitt WR, Reddy KS, Moss AA, Mathur AK. Hospitalizations for Cardiovascular Disease After Liver Transplantation in the United States. Liver Transpl 2018; 24:1398-1410. [PMID: 29544033 DOI: 10.1002/lt.25055] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Revised: 04/30/2018] [Accepted: 03/10/2018] [Indexed: 02/07/2023]
Abstract
Cardiovascular disease (CVD) is a leading cause of post-liver transplant death, and variable care patterns may affect outcomes. We aimed to describe epidemiology and outcomes of inpatient CVD care across US hospitals. Using a merged data set from the 2002-2011 Nationwide Inpatient Sample and the American Hospital Association Annual Survey, we evaluated liver transplant patients admitted primarily with myocardial infarction (MI), stroke (cerebrovascular accident [CVA]), congestive heart failure (CHF), dysrhythmias, cardiac arrest (CA), or malignant hypertension. Patient-level data include demographics, Charlson comorbidity index, and CVD diagnoses. Facility-level variables included ownership status, payer-mix, hospital resources, teaching status, and physician/nursing-to-bed ratios. We used generalized estimating equations to evaluate patient- and hospital-level factors associated with mortality. There were 4763 hospitalizations that occurred in 153 facilities (transplant hospitals, n = 80). CVD hospitalizations increased overall by 115% over the decade (P < 0.01). CVA and MI declined over time (both P < 0.05), but CHF and dysrhythmia grew significantly (both P < 0.03); a total of 19% of hospitalizations were for multiple CVD diagnoses. Transplant hospitals had lower comorbidity patients (P < 0.001) and greater resource intensity including presence of cardiac intensive care unit, interventional radiology, operating rooms, teaching status, and nursing density (all P < 0.01). Transplant and nontransplant hospitals had similar unadjusted mortality (overall, 3.9%, P = 0.55; by diagnosis, all P > 0.07). Transplant hospitals had significantly longer overall length of stay, higher total costs, and more high-cost hospitalizations (all P < 0.05). After risk adjustment, transplant hospitals were associated with higher mortality and high-cost hospitalizations. In conclusion, CVD after liver transplant is evolving and responsible for growing rates of inpatient care. Transplant hospitals are associated with poor outcomes, even after risk adjustment for patient and hospital characteristics, which may be attributable to selective referral of certain patient phenotypes but could also be related to differences in quality of care. Further study is warranted.
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Affiliation(s)
| | - Yu-Hui Chang
- Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery
| | | | - Andrew L Singer
- Transplant Surgery, Department of Surgery, Mayo Clinic School of Medicine, Mayo Clinic Arizona, Phoenix, AZ
| | - Winston R Hewitt
- Transplant Surgery, Department of Surgery, Mayo Clinic School of Medicine, Mayo Clinic Arizona, Phoenix, AZ
| | - Kunam S Reddy
- Transplant Surgery, Department of Surgery, Mayo Clinic School of Medicine, Mayo Clinic Arizona, Phoenix, AZ
| | - Adyr A Moss
- Transplant Surgery, Department of Surgery, Mayo Clinic School of Medicine, Mayo Clinic Arizona, Phoenix, AZ
| | - Amit K Mathur
- Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery.,Transplant Surgery, Department of Surgery, Mayo Clinic School of Medicine, Mayo Clinic Arizona, Phoenix, AZ
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10
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Zhu A, Leto A, Shaked A, Keating B. Immunologic Monitoring to Personalize Immunosuppression After Liver Transplant. Gastroenterol Clin North Am 2018; 47:281-296. [PMID: 29735024 DOI: 10.1016/j.gtc.2018.01.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/21/2023]
Abstract
Although immunosuppressive drugs have enhanced patient outcomes in transplantation, the liver transplant community has made significant research efforts into the discovery of more accurate and precise methods of posttransplant monitoring and diagnosing. Current research in biomarkers reveals many promising approaches.
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Affiliation(s)
- Andrew Zhu
- Division of Transplantation, Department of Surgery, Penn Transplant Institute, The University of Pennsylvania, 3400 Spruce Street, Two Dulles Pavilion, Philadelphia, PA 19104, USA
| | - Alexandra Leto
- Division of Transplantation, Department of Surgery, Penn Transplant Institute, The University of Pennsylvania, 3400 Spruce Street, Two Dulles Pavilion, Philadelphia, PA 19104, USA
| | - Abraham Shaked
- Division of Transplantation, Department of Surgery, Penn Transplant Institute, The University of Pennsylvania, 3400 Spruce Street, Two Dulles Pavilion, Philadelphia, PA 19104, USA.
| | - Brendan Keating
- Division of Transplantation, Department of Surgery, Penn Transplant Institute, The University of Pennsylvania, 3400 Spruce Street, Two Dulles Pavilion, Philadelphia, PA 19104, USA
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11
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Andrade ARCFD, Cotrim HP, Bittencourt PL, Almeida CG, Sorte NCAB. Nonalcoholic steatohepatitis in posttransplantation liver: Review article. ACTA ACUST UNITED AC 2018; 64:187-194. [PMID: 29641680 DOI: 10.1590/1806-9282.64.02.187] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2017] [Accepted: 06/26/2017] [Indexed: 12/17/2022]
Abstract
INTRODUCTION Nonalcoholic steatohepatitis (NASH) associated or not with cirrhosis is the third leading indication for liver transplantation (LT) around the world. After transplants, NASH has a high prevalence and occurs as both recurrent and de novo manifestations. De novo NASH can also occur in allografts of patients transplanted for non-NASH liver disease. OBJECTIVE To evaluate recurrent or de novo NASH in post-LT patients. METHOD A literature review was performed using search engines of indexed scientific material, including Medline (by PubMed), Scielo and Lilacs, to identify articles published in Portuguese and English until August 2016. Eligible studies included: place and year of publication, prevalence, clinical characteristics, risk factors and survival. RESULTS A total of 110 articles were identified and 63 were selected. Most of the studies evaluated recurrence and survival after LT. Survival reached 90-100% in 1 year and 52-100% in 5 years. Recurrence of NAFLD (steatosis) was described in 15-100% and NASH, in 4-71%. NAFLD and de novo NASH were observed in 18-67% and 3-17%, respectively. Metabolic syndrome, diabetes mellitus, dyslipidemia and hypertension were seen in 45-58%, 18-59%, 25-66% and 52-82%, respectively. CONCLUSION After liver transplants, patients present a high prevalence of recurrent and de novo NASH. They also show a high frequence of metabolic disorders. Nevertheless, these alterations seem not to influence patient survival.
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Affiliation(s)
| | - Helma P Cotrim
- Medicine and Health Graduate Program, Faculdade de Medicina da Bahia, Universidade Federal da Bahia, Salvador, BA, Brazil
| | | | - Carolina G Almeida
- Medicine and Health Graduate Program, Faculdade de Medicina da Bahia, Universidade Federal da Bahia, Salvador, BA, Brazil
| | - Ney Christian Amaral Boa Sorte
- Medicine and Health Graduate Program, Faculdade de Medicina da Bahia, Universidade Federal da Bahia, Salvador, BA, Brazil
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12
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Simha V, Qin S, Shah P, Smith BH, Kremers WK, Kushwaha S, Wang L, Pereira NL. Sirolimus Therapy Is Associated with Elevation in Circulating PCSK9 Levels in Cardiac Transplant Patients. J Cardiovasc Transl Res 2016; 10:9-15. [PMID: 28028691 DOI: 10.1007/s12265-016-9719-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Accepted: 11/08/2016] [Indexed: 11/24/2022]
Abstract
Sirolimus used in transplantation is often associated with hypercholesterolemia. We measured serum lipid and PCSK9 levels in 51 heart transplant recipients who had their immunosuppressive therapy switched from calcineurin inhibitors to sirolimus. The switch resulted in a 23% increase in LDL cholesterol, and 46% increase in triglycerides and PCSK9 levels increased from 316 ± 105 ng/mL to 343 ± 107 ng/mL (p = 0.04), however the change in PCSK9 levels did not correlate with an increase in lipid levels (p = 0.2). To investigate the mechanism for the variability in the change in PCSK9 levels, lymphoblastoid cell lines were incubated with both sirolimus and everolimus, resulting in a 2-3 fold increase in PCSK9 expression and protein levels in mTOR inhibitor sensitive but not in mTOR inhibitor resistant cell lines. This first in human study demonstrates that sirolimus therapy is associated with elevation in PCSK9 levels which is not associated with sirolimus-induced hypercholesterolemia.
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Affiliation(s)
- Vinaya Simha
- Division of Endocrinology, Mayo Clinic, Rochester, MN, USA
| | - Sisi Qin
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, 200 First Street SW, Rochester, MN, 55905, USA
| | - Pankaj Shah
- Division of Endocrinology, Mayo Clinic, Rochester, MN, USA
| | - Byron H Smith
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA
| | - Walter K Kremers
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA
| | - Sudhir Kushwaha
- Department of Cardiovascular Diseases, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Liewei Wang
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, 200 First Street SW, Rochester, MN, 55905, USA.
| | - Naveen L Pereira
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, 200 First Street SW, Rochester, MN, 55905, USA. .,Department of Cardiovascular Diseases, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
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13
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Jiménez-Pérez M, González-Grande R, Omonte Guzmán E, Amo Trillo V, Rodrigo López JM. Metabolic complications in liver transplant recipients. World J Gastroenterol 2016; 22:6416-6423. [PMID: 27605877 PMCID: PMC4968123 DOI: 10.3748/wjg.v22.i28.6416] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2016] [Revised: 05/25/2016] [Accepted: 06/13/2016] [Indexed: 02/06/2023] Open
Abstract
The metabolic syndrome (MS), which includes obesity, dyslipidaemia, hypertension and hyperglycaemia according to the most widely accepted definitions now used, is one of the most common post-transplant complications, with a prevalence of 44%-58%. The MS, together with the immunosuppression, is considered the main risk factor for the development of cardiovascular disease (CVD) in transplant recipients, which in turn accounts for 19%-42% of all deaths unrelated to the graft. The presence of MS represents a relative risk for the development of CVD and death of 1.78. On the other hand, non-alcoholic fatty liver disease (NAFLD), considered as the manifestation of the MS in the liver, is now the second leading reason for liver transplantation in the United States after hepatitis C and alcohol. NAFLD has a high rate of recurrence in the liver graft and a direct relation with the worsening of other metabolic disorders, such as insulin resistance or diabetes mellitus. Consequently, it is vitally important to identify and treat as soon as possible such modifiable factors as hypertension, overweight, hyperlipidaemia or diabetes in transplanted patients to thus minimise the impact on patient survival. Additionally, steroid-free regimens are favoured, with minimal immunosuppression to limit the possible effects on the development of the MS.
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Ascha MS, Ascha ML, Hanouneh IA. Management of immunosuppressant agents following liver transplantation: Less is more. World J Hepatol 2016; 8:148-161. [PMID: 26839639 PMCID: PMC4724578 DOI: 10.4254/wjh.v8.i3.148] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2015] [Revised: 09/12/2015] [Accepted: 01/07/2016] [Indexed: 02/06/2023] Open
Abstract
Immunosuppression in organ transplantation was revolutionary for its time, but technological and population changes cast new light on its use. First, metabolic syndrome (MS) is increasing as a public health issue, concomitantly increasing as an issue for post-orthotopic liver transplantation patients; yet the medications regularly used for immunosuppression contribute to dysfunctional metabolism. Current mainstay immunosuppression involves the use of calcineurin inhibitors; these are potent, but nonspecifically disrupt intracellular signaling in such a way as to exacerbate the impact of MS on the liver. Second, the impacts of acute cellular rejection and malignancy are reviewed in terms of their severity and possible interactions with immunosuppressive medications. Finally, immunosuppressive agents must be considered in terms of new developments in hepatitis C virus treatment, which undercut what used to be inevitable viral recurrence. Overall, while traditional immunosuppressive agents remain the most used, the specific side-effect profiles of all immunosuppressants must be weighed in light of the individual patient.
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Abstract
BACKGROUND Liver transplantation is a treatment of choice for both acute and chronic liver failure. Accompanied with the increase of long-term survival rates of recipients, metabolic syndrome and its individual components, including obesity, hyperglycemia, hypertension and hyperlipidemia, have become more frequent post liver transplantation. Here we reviewed the literature concerning the risk factors for the development of metabolic complications in liver recipients. DATA SOURCES PubMed was searched for English-language articles published from January 2000 to June 2015. The search criteria focused on risk factors for metabolic syndrome after liver transplantation. RESULT The risk factors of metabolic syndrome in liver recipients include older age, obesity, pre-transplantation diabetes mellitus, hepatitis C virus infection, certain genetic polymorphisms and the use of immunosuppressive drugs. CONCLUSION Active intervention of the risk factors will reduce the occurrence rate of metabolic syndrome after liver transplantation and improve the recipients' quality of life.
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Affiliation(s)
- Jun Zheng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University School of Medicine; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, China.
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16
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Incidence of cardiovascular and cerebrovascular events associated with sirolimus use after liver transplantation. Transplant Proc 2015; 47:460-4. [PMID: 25769591 DOI: 10.1016/j.transproceed.2014.11.036] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2014] [Accepted: 11/25/2014] [Indexed: 12/16/2022]
Abstract
BACKGROUND Sirolimus (SRL) is an immunosuppressant often used in liver transplantation (LT) to mitigate renal insufficiency associated with calcineurin inhibitors. Sirolimus can cause hyperlipidemia, but its association with coronary artery disease (CAD) and cerebrovascular accidents (CVAs) is unclear. The purpose of this study was to assess the risk of CAD and CVAs with the use of SRL in LT recipients. METHODS We retrospectively reviewed all of our LT recipients from 2000 to 2011. Patients with multiorgan transplant, multiple liver transplants, everolimus therapy, or survival <3 months were excluded. The 803 remaining patients were divided into 3 groups: 1) 134 patients who received and tolerated SRL; 2) 604 patients who never received SRL; and 3) 65 patients who started but discontinued SRL. The primary outcome was the development of CAD or CVA beyond 4 months after transplantation with the use of time-dependent Kaplan-Meier analysis. RESULTS In group 1, there were 6 CAD and 2 CVA events; in group 2, 27 CAD and 16 CVA events; and in group 3, 10 CAD and 2 CVA events. The event-free survival for CAD/CVA at 1, 3, and 5 years was 100%, 98.1%, and 97.2% respectively for group 1; 99.7%, 98.4%, and 96.1% for group 2; and 92.3%, 92.3%, and 85.6% for group 3. On an unadjusted basis, compared with group 2, there was no difference in CAD/CVA rates in group 1 (hazard ratio [HR] 0.92; not significant), but there was an increase in group 3 (HR 2.94; P = .0019). However, on multivariate analysis, only age at transplantation (HR 1.06; P = .001) and diabetes before transplantation (P = .011) were associated with increased CAD/CVA risk. CONCLUSIONS Our analysis showed that patients receiving SRL after LT had no increased risk of CAD/CVA events compared with patients maintained on a calcineurin inhibitor. The risk of CAD/CVA should not be a factor in avoiding SRL.
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Xia Z, Luo XB, Su HB, Sun YL, Min Z, Liu ZW. Refractory Dyslipidemia After Liver Transplant: Case Study With Successive Histologic Investigations. EXP CLIN TRANSPLANT 2015; 13:371-5. [PMID: 25924105 DOI: 10.6002/ect.2014.0051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Hyperlipidemia is not unusual in liver transplant recipients, but refractory severe hyperlipidemia is unusual. We treated a 39-year-old man who had severe dyslipidemia after liver transplant. The levels of blood lipids, liver enzymes, and essential indicators of liver pathology were monitored. The first serum sample was collected from the liver recipient 56 days after transplant surgery because samples could not be obtained sooner after the transplant. The levels of liver enzymes and blood lipids were improved with symptomatic treatment but had recurrent fluctuations. Tacrolimus and cyclosporine, even at low doses, may have been the dominant factor affecting the blood lipid levels in the recipient.
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Affiliation(s)
- Zhou Xia
- From the Department of Transplantation, 302 Hospital, Beijing, China
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18
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Ribeiro HDS, Anastácio LR, Ferreira LG, Lagares EB, Lima AS, Correia MITD. Prevalence and factors associated with dyslipidemia after liver transplantation. Rev Assoc Med Bras (1992) 2015; 60:365-72. [PMID: 25211421 DOI: 10.1590/1806-9282.60.04.016] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2013] [Accepted: 01/13/2014] [Indexed: 01/27/2023] Open
Abstract
OBJECTIVE to determine the prevalence of abnormal total cholesterol (TC), low density lipoprotein (LDL), high density lipoprotein (HDL) and triglycerides in patients undergoing liver transplantation (LTx) and to identify predictors of these disorders. METHODS cross-sectional study to assess the prevalence of dyslipidemia in patients undergoing LTx. Demographic, socioeconomic, clinical, anthropometric and dietetic data were collected to determine the association with dyslipidemia using univariate and multivariate statistical analysis. RESULTS 136 patients were evaluated, 68.1% of which had at least one type of dyslipidemia. The triglyceride level was high in 32.4% of cases, with low HDL in 49.3% of patients and high LDL levels in only 8.8%. High total cholesterol was observed in 16.2% of the study population and was associated with the recommendation for transplantation due to ethanolic cirrhosis (OR = 2.7) and a greater number of hours slept per night (OR = 1.5). CONCLUSION many patients presented dyslipidemia after transplantation, demonstrating the need for interventions in relation to modifiable factors associated with dyslipidemias that can mitigate or prevent these disorders.
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Affiliation(s)
- Hélem de Sena Ribeiro
- Postgraduate Program in Food Science, Faculty of Pharmacy, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Lucilene Rezende Anastácio
- Postgraduate Program in Adult Health, Faculty of Medicine, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Lívia Garcia Ferreira
- Postgraduate Program in Sciences applied to Surgery and Ophthalmology, Faculty of Medicine, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | | | - Agnaldo Soares Lima
- Alfa Institute of Gastroenterology, Hospital das Clínicas, Faculty of Medicine, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
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Mercalli A, Calavita I, Dugnani E, Citro A, Cantarelli E, Nano R, Melzi R, Maffi P, Secchi A, Sordi V, Piemonti L. Rapamycin unbalances the polarization of human macrophages to M1. Immunology 2013; 140:179-90. [PMID: 23710834 DOI: 10.1111/imm.12126] [Citation(s) in RCA: 138] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2013] [Revised: 05/17/2013] [Accepted: 05/21/2013] [Indexed: 12/12/2022] Open
Abstract
Plasticity is a hallmark of macrophages, and in response to environmental signals these cells undergo different forms of polarized activation, the extremes of which are called classic (M1) and alternative (M2). Rapamycin (RAPA) is crucial for survival and functions of myeloid phagocytes, but its effects on macrophage polarization are not yet studied. To address this issue, human macrophages obtained from six normal blood donors were polarized to M1 or M2 in vitro by lipopolysaccharide plus interferon-γ or interleukin-4 (IL-4), respectively. The presence of RAPA (10 ng/ml) induced macrophage apoptosis in M2 but not in M1. Beyond the impact on survival in M2, RAPA reduced CXCR4, CD206 and CD209 expression and stem cell growth factor-β, CCL18 and CCL13 release. In contrast, in M1 RAPA increased CD86 and CCR7 expression and IL-6, tumour necrosis factor-α and IL-1β release but reduced CD206 and CD209 expression and IL-10, vascular endothelial growth factor and CCL18 release. In view of the in vitro data, we examined the in vivo effect of RAPA monotherapy (0·1 mg/kg/day) in 12 patients who were treated for at least 1 month before islet transplant. Cytokine release by Toll-like receptor 4-stimulated peripheral blood mononuclear cells showed a clear shift to an M1-like profile. Moreover, macrophage polarization 21 days after treatment showed a significant quantitative shift to M1. These results suggest a role of mammalian target of rapamycin (mTOR) into the molecular mechanisms of macrophage polarization and propose new therapeutic strategies for human M2-related diseases through mTOR inhibitor treatment.
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Affiliation(s)
- Alessia Mercalli
- Diabetes Research Institute (HSR-DRI), San Raffaele Scientific Institute, Milan, Italy
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20
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Nobili V, de Ville de Goyet J. Pediatric post-transplant metabolic syndrome: new clouds on the horizon. Pediatr Transplant 2013; 17:216-23. [PMID: 23496113 DOI: 10.1111/petr.12065] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/24/2013] [Indexed: 01/15/2023]
Abstract
Liver transplantation (LT) is a standard treatment for children with end-stage liver disease, standing at more than 90% survival rate after one yr, and at over a 70% survival rate after five yr. The majority of transplanted children enjoy an excellent quality of life but complications can occur in the long term, and can develop subclinically in otherwise well children; there are various underestimated nutritional and metabolic aspects, including the so-called post-transplant metabolic syndrome (PTMS). During the post-transplant period, the use of immunosuppressants, corticosteroids, calcineurin inhibitors, and the presence of risk factors, including non-alcoholic fatty liver disease (NAFLD), and kidney and bone complications have been largely implicated in PTMS development. Strategies to reduce the progression of PMTS should include careful screening of patients for diabetes, dyslipidemia, and obesity, and to support weight reduction with a carefully constructed program, particularly based on diet modification and exercise. With early identification and appropriate and aggressive management, excellent long-term health outcomes and acceptable graft survival can be achieved.
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Affiliation(s)
- Valerio Nobili
- Department of Paediatric Surgery and Transplantation Center, Bambino Gesù Children's Hospital, Roma, Italy.
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21
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Kallwitz ER. Metabolic syndrome after liver transplantation: Preventable illness or common consequence? World J Gastroenterol 2012; 18:3627-34. [PMID: 22851856 PMCID: PMC3406416 DOI: 10.3748/wjg.v18.i28.3627] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2012] [Revised: 06/25/2012] [Accepted: 06/28/2012] [Indexed: 02/06/2023] Open
Abstract
The metabolic syndrome is common after liver transplant being present in approximately half of recipients. It has been associated with adverse outcomes such as progression of hepatitis C and major vascular events. As the United States population ages and the rate of obesity increases, prevention of the metabolic syndrome in the post-transplant population deserves special consideration. Currently, the metabolic syndrome after transplant appears at least two times more common than observed rates in the general population. Specific guidelines for patients after transplant does not exist, therefore prevention rests upon knowledge of risk factors and the presence of modifiable elements. The current article will focus on risk factors for the development of the metabolic syndrome after transplant, will highlight potentially modifiable factors and propose potential areas for intervention. As in the non-transplant population, behavioral choices might have a major role. Opportunities exist in this regard for health prevention studies incorporating lifestyle changes. Other factors such as the need for immunosuppression, and the changing characteristics of wait listed patients are not modifiable, but are important to know in order to identify persons at higher risk. Although immunosuppression after transplant is unavoidable, the contribution of different agents to the development of components of the metabolic syndrome is also discussed. Ultimately, an increased risk of the metabolic syndrome after transplant is likely unavoidable, however, there are many opportunities to reduce the prevalence.
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22
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Ai D, Chen C, Han S, Ganda A, Murphy AJ, Haeusler R, Thorp E, Accili D, Horton JD, Tall AR. Regulation of hepatic LDL receptors by mTORC1 and PCSK9 in mice. J Clin Invest 2012; 122:1262-70. [PMID: 22426206 DOI: 10.1172/jci61919] [Citation(s) in RCA: 136] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2011] [Accepted: 02/01/2012] [Indexed: 12/26/2022] Open
Abstract
Individuals with type 2 diabetes have an increased risk of atherosclerosis. One factor underlying this is dyslipidemia, which in hyperinsulinemic subjects with early type 2 diabetes is typically characterized by increased VLDL secretion but normal LDL cholesterol levels, possibly reflecting enhanced catabolism of LDL via hepatic LDLRs. Recent studies have also suggested that hepatic insulin signaling sustains LDLR levels. We therefore sought to elucidate the mechanisms linking hepatic insulin signaling to regulation of LDLR levels. In WT mice, insulin receptor knockdown by shRNA resulted in decreased hepatic mTORC1 signaling and LDLR protein levels. It also led to increased expression of PCSK9, a known post-transcriptional regulator of LDLR expression. Administration of the mTORC1 inhibitor rapamycin caused increased expression of PCSK9, decreased levels of hepatic LDLR protein, and increased levels of VLDL/LDL cholesterol in WT but not Pcsk9-/- mice. Conversely, mice with increased hepatic mTORC1 activity exhibited decreased expression of PCSK9 and increased levels of hepatic LDLR protein levels. Pcsk9 is regulated by the transcription factor HNF1α, and our further detailed analyses suggest that increased mTORC1 activity leads to activation of PKCδ, reduced activity of HNF4α and HNF1α, decreased PCSK9 expression, and ultimately increased hepatic LDLR protein levels, which result in decreased circulating LDL levels. We therefore suggest that PCSK9 inhibition could be an effective way to reduce the adverse side effect of increased LDL levels that is observed in transplant patients taking rapamycin as immunosuppressive therapy.
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Affiliation(s)
- Ding Ai
- Department of Medicine, Columbia University, New York, New York 10032, USA.
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23
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Abstract
Metabolic syndrome (MS) is a cluster of metabolic derangements associated with insulin resistance and an increased risk of cardiovascular mortality. MS has become a major health concern worldwide and is considered to be the etiology of the current epidemic of diabetes and cardiovascular disease. In addition to cardiovascular disease, the presence of MS is also closely associated with other comorbidities including nonalcoholic fatty liver disease (NAFLD). The prevalence of MS in patients with cirrhosis and end-stage liver disease is not well established and difficult to ascertain. Following liver transplant, the prevalence of MS is estimated to be 44-58%. The main factors associated with posttransplant MS are posttransplant diabetes, obesity, dyslipidemia, and hypertension. In addition to developing NAFLD, posttransplant MS is associated with increased cardiovascular mortality that is 2.5 times that of the age- and sex-matched individuals. Additionally, the presence of posttransplant MS has been associated with rapid progression to fibrosis in individuals transplanted for HCV cirrhosis. There is an urgent need for well-designed prospective studies to fully delineate the natural history and risk factors associated with posttransplant MS. Until then, early recognition, prevention, and treatment of its components are vital in improving outcomes in liver transplant recipients.
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Stravitz RT, Carl DE, Biskobing DM. Medical management of the liver transplant recipient. Clin Liver Dis 2011; 15:821-43. [PMID: 22032531 DOI: 10.1016/j.cld.2011.08.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Long-term survival of liver transplant recipients has become the rule rather than the exception. As a result, the medical complications of long-term survival, including atherosclerotic cardiovascular disease, metabolic bone disease, and de novo malignancy, have accounted for an increasing proportion of late morbidity and mortality. Risk factors for these complications begin before transplant and are potentially modifiable but are exacerbated by the requirement for immunosuppressive medications after transplantation. Surveillance and early intervention programs administered by transplant hepatologists and other medical subspecialists may improve long-term outcomes in liver transplant recipients by ameliorating risk factors for atherosclerosis, bone fractures, and cancer.
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Affiliation(s)
- R Todd Stravitz
- Section of Hepatology, Division of Gastroenterology, Hepatology, and Nutrition, Hume-Lee Transplant Center, Virginia Commonwealth University, Richmond, VA 23298-0341, USA.
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25
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Abstract
The introduction of calcineurin inhibitor (CNI) based immunosuppression has revolutionized the field of liver transplantation by dramatically reducing the incidence of acute cellular rejection and prolonging patient and allograft survival. However, the introduction of CNIs has also come at the price of increased patient morbidity, particularly with regard to the well-known nephrotoxic effects of the medications. In an effort to minimize the adverse effects, immunosuppression regimen have evolved to include the use of various induction agents and purine synthesis inhibitors to limit the dose of CNI necessary to achieve low acute cellular rejection rates. Careful assessments of risks and benefits are needed as these newer agents have their own side effect profiles. In addition, the impact of newer immunosuppression regimen on hepatitis C (HCV) recurrence has not been completely elucidated. This review will provide an overview of the most common immunosuppression regimen used in liver transplantation and discuss their impact on acute cellular rejection, patient and allograft survival, and HCV recurrence.
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Affiliation(s)
- Jayme E Locke
- Johns Hopkins Medical institutions, Department of Surgery, Division of Transplantation, Baltimore, MD, USA
| | - Andrew L Singer
- Johns Hopkins Medical institutions, Department of Surgery, Division of Transplantation, Baltimore, MD, USA
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26
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A Decade of Experience Using mTor Inhibitors in Liver Transplantation. J Transplant 2011; 2011:913094. [PMID: 21461386 PMCID: PMC3064995 DOI: 10.1155/2011/913094] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2010] [Revised: 12/20/2010] [Accepted: 01/04/2011] [Indexed: 02/07/2023] Open
Abstract
Some studies suggest that Sirolimus (SRL) is associated with an increased risk of death in liver transplant recipients compared to treatment with calcineurin inhibitors (CNIs). We compared patients who received SRL or CNI in the first year after liver transplant. Our database included 688 patients who received a liver transplant. The patients were divided into groups. (1) CNI + MPS (mycophenolate sodium) at time of discharge. (2) CNI + MPS at time of discharge; SRL was added within the first 6 months and continued through the first year. (3) CNI + MPS at time of discharge; SRL was added within the first 6 months and discontinued before the first year. (4) SRL as primary immunosuppression. (5) SRL as primary immunosuppression and discontinued before the first year. We used mortality and graft loss as the primary measures of outcome. We also quantified renal function using the change in glomerular filtration rate (GFR), the presence of biopsy proven acute cellular reject (ACR), and steroid-resistant rejection (SRR). There were no significant differences in mortality or graft loss. There was no difference in patient or graft survival. Patients that received SRL as primary immunosuppression had 50% less rejection compared to controls.
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27
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Satapathy SK, Charlton MR. Posttransplant metabolic syndrome: new evidence of an epidemic and recommendations for management. Liver Transpl 2011; 17:1-6. [PMID: 21254337 DOI: 10.1002/lt.22222] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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Desai S, Hong JC, Saab S. Cardiovascular risk factors following orthotopic liver transplantation: predisposing factors, incidence and management. Liver Int 2010; 30:948-57. [PMID: 20500807 DOI: 10.1111/j.1478-3231.2010.02274.x] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
BACKGROUND Liver transplantation is the standard of care for acute and chronic causes of end-stage liver disease. Advances in medical therapy and surgical techniques have led to improvement of patient and graft survival rates following orthotopic liver transplantation. However, the prevalence of post-transplant cardiovascular complications has been rising with increased life expectancy after liver transplantation. AIMS To determine the incidences, risk factors, and treatment for hypertension, hyperlipidaemia, diabetes, and obesity in the post-liver transplantation population. METHODS We performed a review of relevant studies available on the PubMed database that provided information on the incidence, risk factors and treatment for cardiovascular complications that develop in the post-liver transplantation population. RESULTS Current immunosuppressive agents have improved patient and graft survival rates. However, long-term exposure to these agents has been associated with development of systemic and metabolic complications including hypertension, hyperlipidaemia, diabetes mellitus and obesity. Cardiovascular disease remains one of the most common causes of death in liver transplant patients with functional grafts. CONCLUSIONS Liver transplant recipients have a higher risk of cardiovascular complications compared with the nontransplant population. Post-transplant cardiac risk stratification and aggressive treatment of cardiovascular complications, including modification of risk factors and tailoring of immunosuppressive regimen, is imperative to prevent serious complications.
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Affiliation(s)
- Shireena Desai
- Department of Medicine, University of California at Los Angeles, Los Angeles, CA, USA
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29
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Watt KDS, Charlton MR. Metabolic syndrome and liver transplantation: a review and guide to management. J Hepatol 2010; 53:199-206. [PMID: 20451282 DOI: 10.1016/j.jhep.2010.01.040] [Citation(s) in RCA: 155] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2009] [Revised: 01/06/2010] [Accepted: 01/09/2010] [Indexed: 12/15/2022]
Abstract
Metabolic syndrome is common among liver transplant recipients before and after transplantation. The components of metabolic syndrome are often exacerbated in the post-transplant period by transplant specific factors, such as immunosuppression, and are strong predictors of patient morbidity and mortality. Many aspects of the metabolic syndrome are modifiable. Early recognition, prevention and treatment of post-transplant hypertension, obesity, dyslipidemia and diabetes may impact long-term post-transplant survival. Further study into the prevention and management of these issues in the transplant patient are needed.
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Affiliation(s)
- Kymberly D S Watt
- Department of Gastroenterology and Hepatology, Mayo Clinic and Foundation, MN, USA
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30
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Metabolic syndrome and its components after liver transplantation: incidence, prevalence, risk factors, and implications. Clin Nutr 2009; 29:175-9. [PMID: 19783330 DOI: 10.1016/j.clnu.2009.08.008] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2008] [Revised: 07/09/2009] [Accepted: 08/14/2009] [Indexed: 01/02/2023]
Abstract
Metabolic syndrome is defined as the mutual existence of obesity, impaired fasting glucose levels, insulin resistance, hypertension, and dyslipidemia. After liver transplantation, patients typically develop these disorders, and even though there has been minimal research focused on the chronic impact of this syndrome on post-liver transplant patients, studies point to an association with major vascular events and fibrosis. The aim of the current work is to review data on the incidence, prevalence, risk factors, and implications of metabolic syndrome and its components in patients who have undergone liver transplantation.
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Molinari M, Berman K, Meeberg G, Shapiro JA, Bigam D, Trotter JF, Kneteman N. Multicentric outcome analysis of sirolimus-based immunosuppression in 252 liver transplant recipients. Transpl Int 2009; 23:155-68. [PMID: 19765266 DOI: 10.1111/j.1432-2277.2009.00969.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
SUMMARY The use of sirolimus (SRL) in orthotopic liver transplantation (OLT) has been controversial after experimental data suggested an increased risk of hepatic artery thrombosis (HAT). To assess the safety and efficacy of SRL as de novo immunosuppression in OLT recipients. Outcomes of 252 OLT patients who received SRL were compared with outcomes of 291 OLT recipients who received calcineurin inhibitor in a retrospective study. Primary outcomes of this study were: patient- and graft survivals, vascular, biliary, wound complications and rejection rates. Secondary outcomes were: postoperative infection rate, bone marrow and renal function and changes of lipid levels. Patient- and graft survivals, rejection and infection rates were similar. In the SRL group, HAT occurred in 1.2%, biliary complications in 19.4%, and incisional hernias in 9.1%. In the control group the incidence of HAT was 5.8% (P = 0.004), biliary complications 18.5% (P = NS) and incisional hernias 7.2% (P = NS). Patients on SRL experienced significantly higher levels of serum triglycerides but fewer acute cellular rejections. Bone marrow and renal functions were similar in both the groups. Our findings would suggest that SRL is safe and effective for very selected OLT recipients. Randomized controlled trials are necessary to confirm our results.
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Affiliation(s)
- Michele Molinari
- Department of Surgery, Dalhousie University Medical Center, Halifax, NS, Canada.
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32
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A comprehensive review of immunosuppression used for liver transplantation. J Transplant 2009; 2009:701464. [PMID: 20130772 PMCID: PMC2809333 DOI: 10.1155/2009/701464] [Citation(s) in RCA: 82] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2009] [Accepted: 05/15/2009] [Indexed: 12/19/2022] Open
Abstract
Since liver transplantation was approved for the treatment of end stage liver disease, calcineurin inhibitors (CNI's) have played a critical role in the preservation of allograft function. Unfortunately, these medications cause a variety of Side effects such as diabetes, hypertension and nephrotoxicity which in turn result in significant morbidity and reduced quality of life. A variety of newer immunosuppressants have been evaluated over the last decade in an attempt to either substitute for CNI's or use with reduced dose CNI's while still preserving allograft function However, current data does not recommend complete cessation of CNI's due to unacceptably high rates of allograft rejection. As these medications have their own unique adverse effects, a careful assessment on their risks and benefits is essential, particularly when additive or synergistic effects with CNI's may occur. Furthermore, the impact of these newer medications on the risk of hepatitis C recurrence and progression remains to be elucidated. Controlled trials are urgently required to assist transplant physicians with choosing the optimum immunosuppressive regimen for their patients. This review will discuss commonly used immunosuppressants prescribed in liver transplantation, emerging therapties and where appropriate, the impact of these medications on the recurrence of hepatitis C after liver transplantation.
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Subramanian S, Trence DL. Immunosuppressive agents: effects on glucose and lipid metabolism. Endocrinol Metab Clin North Am 2007; 36:891-905; vii. [PMID: 17983927 DOI: 10.1016/j.ecl.2007.07.003] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Immunosuppressive therapies are critical elements in successful organ transplantation. Although immunosuppressant drugs are essential in preventing graft rejection and graft maintenance after transplantation, their use is complicated by adverse effects, many being detrimental to graft and even patient long-term survival. Commonly used agents are associated with dysregulated glucose metabolism and dyslipidemia. This article focuses on the effects of immunosuppressive agents on glucose and lipid metabolism. Adrenal effects of these drugs, where known, also are discussed.
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Affiliation(s)
- Savitha Subramanian
- Division of Metabolism, Endocrinology and Nutrition, University of Washington, Box 356426, 1959 NE Pacific Street, Seattle, WA 98195, USA
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Niemann CU, Serkova NJ. Biochemical mechanisms of nephrotoxicity: application for metabolomics. Expert Opin Drug Metab Toxicol 2007. [DOI: 10.1517/17425255.3.4.527] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Toso C, Meeberg GA, Bigam DL, Oberholzer J, Shapiro AMJ, Gutfreund K, Ma MM, Mason AL, Wong WWS, Bain VG, Kneteman NM. De novo sirolimus-based immunosuppression after liver transplantation for hepatocellular carcinoma: long-term outcomes and side effects. Transplantation 2007; 83:1162-8. [PMID: 17496530 DOI: 10.1097/01.tp.0000262607.95372.e0] [Citation(s) in RCA: 146] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND We report long-term outcomes and side effects after transplantation for hepatocellular carcinoma (HCC) using de novo, sirolimus-based immunosuppression (IS). METHODS A total of 70 patients with HCC (mean age: 54.4+/-7 years, female/male: 12/58) were transplanted and included in the study. Immunosuppression included de novo sirolimus, low-dose calcineurin inhibitor for 6 to 12 months, with short-course (3 months) or no steroids. RESULTS After 49 months-median follow-up, eight patients have experienced an HCC recurrence, 2 of 34 when Milan criteria were respected (6%) and 6 of 36 when beyond Milan criteria (17%). One- and 4-year tumor-free survivals were 85 and 73%, when Milan criteria were respected and 82% and 75% when they were not, respectively. (P=0.9). After recurrence, mean survival was 23+/-28 months. Half (35 of 70) of the patients experienced a rejection. Incisional hernia (24 of 70, 34%), wound infection (12 of 70, 17%), anemia (39 of 70, 56%), leucopenia (39 of 70, 56%), high triglyceride (43 of 70, 61%), and cholesterol (28 of 70, 40%) levels and mouth ulcers (20 of 70, 29%) were among the most frequent complications. No hepatic artery thrombosis was observed. CONCLUSIONS These data suggest that de novo sirolimus-based immunosuppression is associated with satisfactory outcomes after transplantation, even in selected patients beyond Milan criteria. The protocol has proven safe, with an acceptable side-effect profile. This study supports the conduct of larger randomized trials investigating sirolimus after transplantation for HCC.
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Affiliation(s)
- Christian Toso
- Department of Surgery, Section of Hepatobiliary, Pancreatic and Transplant Surgery, University of Alberta, Edmonton, Canada
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Abstract
As survival increases after liver transplantation, common issues that arise involve immunosuppression-related complications and primary health care. Proper emphasis on the prevention and treatment of post-liver transplant complications, such as diabetes mellitus, dyslipidemia, renal dysfunction, osteoporosis, and obesity, requires careful screening and long-term surveillance to minimize the progression of these complications. Active involvement by internists and subspecialists is necessary and a multidisciplinary approach should be undertaken. Liver transplantation should be viewed as a lifelong commitment by both patient and physician.
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Affiliation(s)
- Lawrence U Liu
- Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1104, New York, NY 10029, USA.
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Sethi A, Stravitz RT. Review article: medical management of the liver transplant recipient - a primer for non-transplant doctors. Aliment Pharmacol Ther 2007; 25:229-45. [PMID: 17217455 DOI: 10.1111/j.1365-2036.2006.03166.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Survival 10 years after orthotopic liver transplantation now approaches 65%. Consequently, community doctors must manage the metabolic and neoplastic complications of orthotopic liver transplantation in an ageing population. AIMS To review common sources of morbidity and mortality in long-term orthotopic liver transplantation recipients, and to make evidence-based recommendations regarding their management. METHODS Pertinent studies and reviews were identified by literature search through PubMed. Where evidence-based recommendations could not be gleaned from the literature, expert opinion was obtained from syllabi of national meetings. RESULTS The two most common causes of morbidity and mortality in orthotopic liver transplantation recipients are atherosclerotic vascular disease and de novo malignancy. The pathogenesis of many complications begins before orthotopic liver transplantation, and many are potentially modifiable. Most complications, however, can be directly ascribed to immunosuppressive agents. Despite improvements in our understanding of the pathogenesis and epidemiology of the metabolic and neoplastic complications of orthotopic liver transplantation, remarkably few randomized-controlled studies exist to define their optimal management. CONCLUSIONS Orthotopic liver transplantation recipients experience and succumb to the same afflictions of old age as non-transplant patients, but with greater frequency and at an earlier age. Most recommendations regarding surveillance for, and treatment of, medical complications of orthotopic liver transplantation remain based upon expert opinion rather than evidence-based medicine.
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Affiliation(s)
- A Sethi
- Section of Hepatology and Liver Transplant Program, Virginia Commonwealth University, Richmond, VA 23298-0341, USA
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Mercalli A, Sordi V, Ponzoni M, Maffi P, De Taddeo F, Gatti G, Servida P, Bernardi M, Bellio L, Bertuzzi F, Secchi A, Bonifacio E, Piemonti L. Rapamycin induces a caspase-independent cell death in human monocytes. Am J Transplant 2006; 6:1331-41. [PMID: 16686757 DOI: 10.1111/j.1600-6143.2006.01332.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
The immunosuppressive activity of rapamycin (RAPA) and its efficacy as an anti-rejection agent in organ transplantation have been ascribed principally to its anti-proliferative effects on T cells, while the activity on monocytes is partially unknown. In vitro, RAPA reduced monocyte survival by inducing a caspase-independent cell death. RAPA-induced monocyte cell death (RAPA-CD) was impeded by activation of granulocyte macrophage-colony stimulating factor family receptors or toll-like receptor 4, and by exposure to inflammatory cytokines. In vivo, in patients who received RAPA monotherapy as part of pre-conditioning for islet transplantation, RAPA affected survival of myeloid lineage cells. In the peripheral blood, CD33(+) and CD14(+) cells decreased, whereas lymphocytes appeared unaffected. In the bone marrow, myeloid precursors such as CD15(+) and CD15(+)/CD16(+) were selectively and significantly decreased, but no major cytotoxic effects were observed. The RAPA-CD suggests a dependence of monocytes on mammalian target of RAPA pathways for nutrient usage, and this feature implies that RAPA could be selectively useful as a treatment to reduce monocytes or myeloid cells in conditions where these cells negatively affect patient, suggesting a potential anti-inflammatory action of this drug.
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Affiliation(s)
- A Mercalli
- Immunology of Diabetes Unit, San Raffaelle Scientific Institute, via Olgettina 60, 20132 Milan, Italy
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Watson CJ, Bradley JA. Sirolimus and everolimus: inhibitors of mammalian target of rapamycin in liver transplantation. Transplant Rev (Orlando) 2006. [DOI: 10.1016/j.trre.2006.06.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
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Sanchez EQ, Martin AP, Ikegami T, Uemura T, Narasimhan G, Goldstein RM, Levy MF, Chinnakotla S, Dawson S, Randall HB, Saracino G, Klintmalm GB, Klintmaim GB. Sirolimus conversion after liver transplantation: improvement in measured glomerular filtration rate after 2 years. Transplant Proc 2006; 37:4416-23. [PMID: 16387135 DOI: 10.1016/j.transproceed.2005.10.019] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2005] [Indexed: 01/09/2023]
Abstract
METHODS We reviewed our prospectively maintained database of 2005 liver transplantations. Therapy was either started de novo or converted from calcineurin inhibitors (CNIs) to sirolimus as the main immunosuppressive agent for nephrotoxicity or rejection. Glomerular filtration rate (GFR) was determined with iodine 125-labeled sodium isthalamate (Glofil-125), and serum creatinine concentration was obtained before and 3 months after transplantation, and yearly in both groups. Sirolimus levels were 10 to 15 ng/mL in patients at less than 3 months after transplantations and 5 to 10 ng/mL in the remaining patients. All patients received mycophenolate mofetil as maintenance therapy. RESULTS Data for 29 patients in the de novo group and 35 in the conversion group were reviewed. Patients in the de novo group demonstrated an acute cellular rejection rate of 17.2%, 40% of which were steroid resistant. In this group, 48.2% discontinuation of sirolimus was necessary because of adverse effects. Patients in the conversion group demonstrated an acute cellular rejection rate of 2.8% and a 34.3% rate of sirolimus discontinuation. Seventeen (56.7%) patients at 1 year and 8 (44.4%) patients at 2 years demonstrated continued improvement in GFR. In the conversion group, case-control analysis did not demonstrate a significant difference in GFR and serum creatinine concentration (P > .05) at 1 and 2 years after conversion. At the time of review, no patients in the conversion group required hemodialysis. CONCLUSIONS Conversion to sirolimus therapy is an effective strategy in improving renal function in patients with CNI-induced nephrotoxicity and can be done without increased rejection. Most of our patients (65.7%) tolerated sirolimus conversion. Of these, 56.7% and 44.4% demonstrated continued increase in GFR with the CNI-free regimen at 1 and 2 years, respectively. Long-term, large-population, prospective, randomized, controlled studies should further validate these results.
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Affiliation(s)
- E Q Sanchez
- Transplantation Services, Baylor University Medical Center, Dallas, Texas 75246, USA.
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Zaghla H, Selby RR, Chan LS, Kahn JA, Donovan JA, Jabbour N, Genyk Y, Mateo R, Gagandeep S, Sher LS, Ramicone E, Fong TL. A comparison of sirolimus vs. calcineurin inhibitor-based immunosuppressive therapies in liver transplantation. Aliment Pharmacol Ther 2006; 23:513-20. [PMID: 16441472 DOI: 10.1111/j.1365-2036.2006.02770.x] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
BACKGROUND Sirolimus is a potent immunosuppressive agent whose role in liver transplantation has not been well-described. AIM To evaluate the efficacy and side-effects of sirolimus-based immunosuppression in liver transplant patients. METHODS Retrospective analysis of 185 patients who underwent orthotopic liver transplantation. Patients were divided into three groups: group SA, sirolimus alone (n = 28); group SC, sirolimus with calcineurin inhibitors (n =56) and group CNI, calcineurin inhibitors without sirolimus (n = 101). RESULTS One-year patient and graft survival rates were 86.5% and 82.1% in group SA, 94.6% and 92.9% in group SC, and 83.2% and 75.2% in group CNI (P = N.S.). The rates of acute cellular rejection at 12 months were comparable among the three groups. At the time of transplantation, serum creatinine levels were significantly higher in group SA, but mean creatinine among the three groups at 1 month was similar. More patients in group SA required dialysis before orthotopic liver transplantation (group SA, 25%; group SC, 9%; group CNI, 5%; P = 0.008), but at 1 year, post-orthotopic liver transplantation dialysis rates were similar. CONCLUSIONS Sirolimus given alone or in conjunction with calcineurin inhibitors appears to be an effective primary immunosuppressant regimen for orthotopic liver transplantation patients. Further studies to evaluate the efficacy and side-effect profile of sirolimus in liver transplant patients are warranted.
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Affiliation(s)
- H Zaghla
- Liver Transplant Program, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA
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Ryan EA, Paty BW, Senior PA, Bigam D, Alfadhli E, Kneteman NM, Lakey JRT, Shapiro AMJ. Five-year follow-up after clinical islet transplantation. Diabetes 2005; 54:2060-9. [PMID: 15983207 DOI: 10.2337/diabetes.54.7.2060] [Citation(s) in RCA: 1183] [Impact Index Per Article: 59.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Islet transplantation can restore endogenous beta-cell function to subjects with type 1 diabetes. Sixty-five patients received an islet transplant in Edmonton as of 1 November 2004. Their mean age was 42.9 +/- 1.2 years, their mean duration of diabetes was 27.1 +/- 1.3 years, and 57% were women. The main indication was problematic hypoglycemia. Forty-four patients completed the islet transplant as defined by insulin independence, and three further patients received >16,000 islet equivalents (IE)/kg but remained on insulin and are deemed complete. Those who became insulin independent received a total of 799,912 +/- 30,220 IE (11,910 +/- 469 IE/kg). Five subjects became insulin independent after one transplant. Fifty-two patients had two transplants, and 11 subjects had three transplants. In the completed patients, 5-year follow-up reveals that the majority ( approximately 80%) have C-peptide present post-islet transplant, but only a minority ( approximately 10%) maintain insulin independence. The median duration of insulin independence was 15 months (interquartile range 6.2-25.5). The HbA(1c) (A1C) level was well controlled in those off insulin (6.4% [6.1-6.7]) and in those back on insulin but C-peptide positive (6.7% [5.9-7.5]) and higher in those who lost all graft function (9.0% [6.7-9.3]) (P < 0.05). Those who resumed insulin therapy did not appear more insulin resistant compared with those off insulin and required half their pretransplant daily dose of insulin but had a lower increment of C-peptide to a standard meal challenge (0.44 +/- 0.06 vs. 0.76 +/- 0.06 nmol/l, P < 0.001). The Hypoglycemic score and lability index both improved significantly posttransplant. In the 128 procedures performed, bleeding occurred in 15 and branch portal vein thrombosis in 5 subjects. Complications of immunosuppressive therapy included mouth ulcers, diarrhea, anemia, and ovarian cysts. Of the 47 completed patients, 4 required retinal laser photocoagulation or vitrectomy and 5 patients with microalbuminuria developed macroproteinuria. The need for multiple antihypertensive medications increased from 6% pretransplant to 42% posttransplant, while the use of statin therapy increased from 23 to 83% posttransplant. There was no change in the neurothesiometer scores pre- versus posttransplant. In conclusion, islet transplantation can relieve glucose instability and problems with hypoglycemia. C-peptide secretion was maintained in the majority of subjects for up to 5 years, although most reverted to using some insulin. The results, though promising, still point to the need for further progress in the availability of transplantable islets, improving islet engraftment, preserving islet function, and reducing toxic immunosuppression.
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Affiliation(s)
- Edmond A Ryan
- Department of Medicine, Clinical Islet Transplant Program, 2000 College Plaza, 8215 112th St., Edmonton, Alberta, Canada T6G 2C8.
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Lucey MR, Abdelmalek MF, Gagliardi R, Granger D, Holt C, Kam I, Klintmalm G, Langnas A, Shetty K, Tzakis A, Woodle ES. A comparison of tacrolimus and cyclosporine in liver transplantation: effects on renal function and cardiovascular risk status. Am J Transplant 2005; 5:1111-9. [PMID: 15816894 DOI: 10.1111/j.1600-6143.2005.00808.x] [Citation(s) in RCA: 73] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
A retrospective chart review of 1065 consecutive liver allograft recipients in 11 centers from January 1997 to September 1998 was performed. Patients were followed for 3 years or until graft loss. Patients received either tacrolimus (n = 594), cyclosporine (n = 450) or no calcineurin inhibitor (n = 21). Model for end-stage liver disease (MELD) scores at time of transplant were similar between the two groups. During follow-up, more patients switched from cyclosporine to tacrolimus (26.7%) than from tacrolimus to cyclosporine (12.8%; p < 0.0001). Patient and graft survival were equivalent. Corticosteroid use was more common in cyclosporine-treated patients (p < 0.00001). Patients receiving tacrolimus experienced lower serum creatinine levels at months 3 through 36 (p < 0.0001). Systolic blood pressure was lower in patients receiving tacrolimus (p < 0.001) despite a reduced requirement for anti-hypertensive agents (p < 0.0001). In addition, tacrolimus was associated with lower total cholesterol and triglyceride levels for months 3 through 24 and 3 through 12, respectively (p < 0.01), despite a reduced requirement for anti-hyperlipidemic agents. The incidence of new-onset diabetes mellitus was similar in both groups. While both calcineurin inhibitors were associated with excellent patient and graft survival, renal function, blood pressure and serum lipid levels were significantly better with tacrolimus treatment.
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Kerkar N, Dugan C, Rumbo C, Morotti RA, Gondolesi G, Shneider BL, Emre S. Rapamycin successfully treats post-transplant autoimmune hepatitis. Am J Transplant 2005; 5:1085-9. [PMID: 15816890 DOI: 10.1111/j.1600-6143.2005.00801.x] [Citation(s) in RCA: 99] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Rapamycin (Rapa), one of the newer immunosuppressants has been found to control and prevent autoimmune features in animal models. This is the first report describing the successful control of post-transplant autoimmune hepatitis (AIH) with Rapa. Post-transplant AIH is diagnosed in the presence of raised transaminases, elevated immunoglobulin G, presence of autoantibodies and histologic changes consistent with AIH on liver biopsy. It may represent a recurrence of the original AIH that led to transplantation or present as a de novo AIH after liver transplant. Post-transplant AIH has conventionally been treated with Prednisolone (Pred) and Azathioprine (AZA). In this report, tailoring of immunosuppression after diagnosis of post-transplant AIH is described with special emphasis on those treated successfully with Rapa. Fifteen of 21 patients responded to treatment with an increase in dose of Pred and addition of AZA or Mycophenolate Mofetil (MMF) to calcineurin inhibitor. Five non-responders and one other patient with post-transplant AIH were treated with addition of Rapa. All six responded to treatment but drug was withdrawn in one patient. Adverse events were minimal. Rapa may prove to be an important addition in the control of autoimmune liver disease.
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Affiliation(s)
- Nanda Kerkar
- Recanati Miller Transplant Institute, Department of Pediatrics, Division of Pediatric Hepatology, The Mount Sinai School of Medicine, New York, NY, USA
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Abstract
Sirolimus (rapamycin) is a macrocyclic lactone isolated from a strain of Streptomyces hygroscopicus that inhibits the mammalian target of rapamycin (mTOR)-mediated signal-transduction pathways, resulting in the arrest of cell cycle of various cell types, including T- and B-lymphocytes. Sirolimus has been demonstrated to prolong graft survival in various animal models of transplantation, ranging from rodents to primates for both heterotopic, as well as orthotopic organ grafting, bone marrow transplantation and islet cell grafting. In human clinical renal transplantation, sirolimus in combination with ciclosporin (cyclosporine) efficiently reduces the incidence of acute allograft rejection. Because of the synergistic effect of sirolimus on ciclosporin-induced nephrotoxicity, a prolonged combination of the two drugs inevitably leads to progressive irreversible renal allograft damage. Early elimination of calcineurin inhibitor therapy or complete avoidance of the latter by using sirolimus therapy is the optimal strategy for this drug. Prospective randomised phase II and III clinical studies have confirmed this approach, at least for recipients with a low to moderate immunological risk. For patients with a high immunological risk or recipients exposed to delayed graft function, sirolimus might not constitute the best therapeutic choice--despite its ability to enable calcineurin inhibitor sparing in the latter situation--because of its anti-proliferative effects on recovering renal tubular cells. Whether lower doses of sirolimus or a combination with a reduced dose of tacrolimus would be advantageous in these high risk situations remains to be determined. Clinically relevant adverse effects of sirolimus that require a specific therapeutic response or can potentially influence short- and long-term patient morbidity and mortality as well as graft survival include hypercholesterolaemia, hypertriglyceridaemia, infectious and non-infectious pneumonia, anaemia, lymphocele formation and impaired wound healing. These drug-related adverse effects are important determinants in the choice of a tailor-made immunosuppressive drug regimen that complies with the individual patient risk profile. Equally important in the latter decision is the lack of severe intrinsic nephrotoxicity associated with sirolimus and its advantageous effects on arterial hypertension, post-transplantation diabetes mellitus and esthetic changes induced by calcineurin inhibitors. Mild and transient thrombocytopenia, leukopenia, gastrointestinal adverse effects and mucosal ulcerations are all minor complications of sirolimus therapy that have less impact on the decision for choosing this drug as the basis for tailor-made immunosuppressive therapy. It is clear that sirolimus has gained a proper place in the present-day immunosuppressive armament used in renal transplantation and will contribute to the development of a tailor-made immunosuppressive therapy aimed at fulfilling the requirements outlined by the individual patient profile.
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Affiliation(s)
- Dirk R J Kuypers
- Department of Nephrology and Renal Transplantation, University Hospitals Leuven, University of Leuven, B-3000 Leuven, Belgium.
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Abstract
Islet transplantation can deliver stable glycemic control, relief from recurrent severe hypoglycemia, and insulin independence. Accessing the portal vein via the percutaneous hepatic approach carries the risk of bleeding, and the infusion of islets a risk of portal vein thrombosis. In the long term, common minor problems with immunosuppression are mouth ulcers, diarrhea, and acne. Longer-term risks include malignancy and serious infection, both rare to date in clinical islet transplantation. Sensitization to donor antigens may also occur. The long-term diabetes complications may stabilize, but of this aspect little is known to date. In the short term, there may be some elevation of serum cholesterol and blood pressure, in some patients there has been a decline in renal function, and in a few, acute retinal bleeds. For most, improvement in glucose control with resolution of glycemic lability and hypoglycemia has been a net benefit.
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Affiliation(s)
- Edmond A Ryan
- Clinical Islet Transplant Program, 2000 College Plaza, 8215 112th Street, Edmonton, Alberta T6G 2C8, Canada.
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50
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Abstract
Once regarded as a last-resort therapy for patients with end-stage liver disease, liver transplantation has become a viable therapeutic option because of sweeping improvements in surgical techniques and the development of more powerful immunosuppressive agents. The addition of tacrolimus to the immunosuppression regimen represents a highly potent therapy and a powerful defense against acute rejection. In the decade since tacrolimus was approved for use in the United States, it has become a widely used immunosuppressant in the field of liver transplantation.
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Affiliation(s)
- Ronald W Busuttil
- Division of Liver and Pancreas Transplant, Department of Surgery, UCLA School of Medicine, Los Angeles, CA, USA
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