scholarly journals The Role of mTOR Inhibitors in Liver Transplantation: Reviewing the Evidence

2014 ◽  
Vol 2014 ◽  
pp. 1-45 ◽  
Author(s):  
Goran B. Klintmalm ◽  
Björn Nashan
Keyword(s):  
Metabolic Syndrome ◽  
Liver Transplantation ◽  
Renal Function ◽  
De Novo ◽  
Immunosuppressive Agents ◽  
Mammalian Target Of Rapamycin ◽  
Calcineurin Inhibitors ◽  
Mtor Inhibitors

Despite the success of liver transplantation, long-term complications remain, includingde novomalignancies, metabolic syndrome, and the recurrence of hepatitis C virus (HCV) and hepatocellular carcinoma (HCC). The current mainstay of treatment, calcineurin inhibitors (CNIs), can also worsen posttransplant renal dysfunction, neurotoxicity, and diabetes. Clearly there is a need for better immunosuppressive agents that maintain similar rates of efficacy and renal function whilst minimizing adverse effects. The mammalian target of rapamycin (mTOR) inhibitors with a mechanism of action that is different from other immunosuppressive agents has the potential to address some of these issues. In this review we surveyed the literature for reports of the use of mTOR inhibitors in adult liver transplantation with respect to renal function, efficacy, safety, neurological symptoms,de novotumors, and the recurrence of HCC and HCV. The results of our review indicate that mTOR inhibitors are associated with efficacy comparable to CNIs while having benefits on renal function in liver transplantation. We also consider newer dosing schedules that may limit side effects. Finally, we discuss evidence that mTOR inhibitors may have benefits in the oncology setting and in relation to HCV-related allograft fibrosis, metabolic syndrome, and neurotoxicity.

scholarly journals Cardiovascular and Metabolic Consequences of Liver Transplantation: A Review

Medicina ◽  
2019 ◽  
Vol 55 (8) ◽  
pp. 489
Author(s):  
Plotogea ◽  
Ilie ◽  
Sandru ◽  
Chiotoroiu ◽  
Bratu ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Liver Transplantation ◽  
De Novo ◽  
Current Knowledge ◽  
Morbidity And Mortality ◽  
High Morbidity ◽  
Term Survival ◽  
The Metabolic Syndrome ◽  
Acute Liver Disease

Liver transplantation (LT) is considered the curative treatment option for selected patients who suffer from end-stage or acute liver disease or hepatic malignancy (primary). After LT, patients should be carefully monitored for complications that may appear, partially due to immunosuppressive therapy, but not entirely. Cardiovascular diseases are frequently encountered in patients with LT, being responsible for high morbidity and mortality. Patients with underlying cardiovascular and metabolic pathologies are prone to complications after the transplant, but these complications can also appear de novo, mostly associated with immunosuppressants. Metabolic syndrome, defined by obesity, hypertension, dyslipidemia, and hyperglycemia, is diagnosed among LT recipients and is aggravated after LT, influencing the long-term survival. In this review, our purpose was to summarize the current knowledge regarding cardiovascular (CV) diseases and the metabolic syndrome associated with LT and to assess their impact on short and long-term morbidity and mortality.

scholarly journals Cardiovascular involvement after liver transplantation: role of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis

2021 ◽  
Author(s):  
Rosa Lombardi ◽  
Giuseppina Pisano ◽  
Silvia Fargion ◽  
Anna Ludovica Fracanzani
Keyword(s):  
Metabolic Syndrome ◽  
Liver Transplantation ◽  
Liver Disease ◽  
High Risk ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Fatty Liver Disease

Patients submitted to liver transplantation (LT) are exposed to high risk of cardiovascular (CV) complications which are the main determinants of both short-term and long-term morbidity and mortality in LT. Non-alcoholic fatty liver disease (NAFLD) is a very frequent condition in general population and is associated with a high risk of cardiovascular disease (CVD) which represents the first cause of death of these patients. NAFLD is predicted to become the first indication to LT and nowadays is also frequently detected in patients submitted to LT for other indications. Thus, the risk of CVD in patients submitted to LT is forecasted to increase in the next years. In this review the extent of CV involvement in patients submitted to LT and the role of NAFLD, either recurring after transplantation or as de novo presentation, in increasing CV risk is analysed. The risk of developing metabolic alterations, including diabetes, hypertension, dyslipidemia and weight gain, all manifestations of metabolic syndrome, occurring in the first months after LT, is depicted. The different presentations of cardiac involvement, represented by early atherosclerosis, coronary artery disease, heart failure and arrhythmias in patients with NAFLD submitted to LT is described. In addition, the tools to detect cardiac alterations either before or after LT is reported providing the possibility for an early diagnosis of CVD and an early therapy able to reduce morbidity and mortality for these diseases. The need for long-term concerted multidisciplinary activity with dietary counseling and exercise combined with drug treatment of all manifestations of metabolic syndrome is emphasized.

scholarly journals Effect of cyclosporin and tacrolimus on kidney function in liver recipients

2018 ◽  
Vol 4 (3) ◽  
pp. 37-42
Author(s):  
Elena Kosmacheva ◽  
Anna Babich
Keyword(s):  
Chronic Kidney Disease ◽  
Liver Transplantation ◽  
Renal Function ◽  
Glomerular Filtration Rate ◽  
Kidney Disease ◽  
Glomerular Filtration ◽  
Kidney Function ◽  
Filtration Rate ◽  
Calcineurin Inhibitors

Introduction. Chronic renal failure is a significant issue regarding treatment of patients after liver transplantation. One of the factors determining the impaired renal function after liver transplantation is a long-term immunosuppressive therapy based on calcineurin inhibitors. The objective of the study was to evaluate the dynamics of renal function, depending on the use of various calcineurin inhibitors in the long-term postoperative period in liver recipients in real clinical practice. Materials and methods. A retrospective analysis of the renal function in patients operated in the State Public Health Budget Institution “Scientific Research Institute – S.V. Ochapovsky Regional Clinic Hospital № 1”, Krasnodar Region, was carried out. This article describes dynamics of creatinine level and glomerular filtration rate (GFR) in patients before liver transplant, as well as 6 months, 1, 2 and 3 years after surgery. GFR was calculated using the CKD-EPI formula (Chronic Kidney Disease Epidemiology Collaboration). Statistical processing of the results was carried out using the Statistica 10 software package. Results and discussion. Before transplantation, the level of creatinine in the blood plasma was 82.9±19.8 mmol/l, 6 months later a20.4% increase in creatinine was registered (p=0.004), 12, 24 and 36 months later – it increased by 24.8% (p=0.00001), 24.4% (p=0.0004), and 26.0% (p=0.0005), respectively. Both cyclosporine and tacrolimus caused an increase in the level of creatinine. Baseline GFR was 83.4±25.9, the reduction in GFR occurred in comparison with the baseline by 14.2% (p=0.0005), 18.8% (p=0.00001), 20.2% (p=0.00003), 22.6% % (p=0.00006) 6, 12, 24 and 36 months later, respectively. The degree of the decrease in GFR against the background of tacrolimus therapy did not differ significantly from that in case of cyclosporine. Verification of chronic kidney disease and the administration of statins were recorded in isolated cases. Conclusions. In liver recipients, the level of creatinine rises and GFR decreases. Reduction of kidney function occurs against the background of both inhibitors of calcineurin, in connection with which it is necessary to increase the doctors’ alertness for early detection of a decrease in glomerular filtration rate with further verification of chronic kidney disease.

Immunosuppressants and Antiretroviral Therapy in HIV-Positive Transplant Patients

2017 ◽  
Author(s):  
Carolyn Kramer ◽  
Emily Blumberg
Keyword(s):  
Antiretroviral Therapy ◽  
Immunosuppressive Agents ◽  
Mammalian Target Of Rapamycin ◽  
Calcineurin Inhibitors ◽  
Mtor Inhibitors ◽  
Integrase Inhibitor ◽  
Hiv Positive ◽  
Transplant Recipients ◽  
Therapy Regimen ◽  
Transplant Patients

Protease inhibitors (PIs), especially ritonavir, are inhibitors of CYP3A4 and P-gp1 and can significantly increase levels of calcineurin inhibitors and mammalian target of rapamycin (mTOR) inhibitors. Cobicistat is an inhibitor of CYP3A4, and its effect on levels of calcineurin inhibitors and mTOR inhibitors is likely to be similar to that of ritonavir. Efavirenz may result in lower concentrations of calcineurin inhibitors and mTOR inhibitors. Dose reduction and careful attention to monitoring drug levels are critical to avoid toxicity and maintain therapeutic immunosuppressive concentrations when PIs or cobicistat are coadministered with calcineurin inhibitors or mTOR inhibitors. Although there is no formalized recommendation for the ideal antiretroviral therapy regimen in HIV-positive transplant recipients, a regimen consisting of two nucleoside reverse transcriptase and an integrase inhibitor minimizes the risk of drug–drug interactions and simplifies dosing of immunosuppressive agents while maintaining a high barrier to resistance.

scholarly journals The effect of early everolimus administration on the renal function while reducing the dosage of calcineurin inhibitors in liver transplant recipients in a long-term follow-up

2021 ◽  
Vol 13 (2) ◽  
pp. 121-129
Author(s):  
V. E. Syutkin ◽  
A. A. Salienko ◽  
O. D. Olisov ◽  
S. V. Zhuravel ◽  
M. S. Novruzbekov
Keyword(s):  
Liver Transplantation ◽  
Renal Function ◽  
Glomerular Filtration Rate ◽  
Liver Transplant ◽  
Glomerular Filtration ◽  
Filtration Rate ◽  
Calcineurin Inhibitors ◽  
Transplant Recipients ◽  
Liver Transplant Recipients

Introduction. The lifelong use of calcineurin inhibitors in liver transplant recipients leads to an increased incidence of chronic kidney disease.Objective. To compare the changes in glomerular filtration rate over five years in liver transplant recipients between those on everolimus with a reduced exposure to calcineurin inhibitors and those on standard doses of calcineurin inhibitors.Material and methods. Fourteen liver transplant recipient switched to everolimus with a minimization of calcineurin inhibitors exposure in the first months after liver transplantation from February 2009 to February 2015 who had received that therapy continuously for at least 60 months were included in the case-control study. Twenty eight liver transplant recipients (matched by sex, etiology of the underlying disease, calcineurin inhibitors) who were followed-up for at least 60 months after liver transplantation, who had received no dose of everolimus, in whom the glomerular filtration rate could be calculated at all points of analysis were selected as a comparison group (1:2). Glomerular filtration rate was calculated immediately before liver transplantation; 12, 24, 36, 48, and 60 months after liver transplantation. The glomerular filtration rate after liver transplantation was also calculated for liver transplant recipients from the main group immediately before the conversion to everolimus.Results. Before liver transplantation, the median of glomerular filtration rate in the main group of liver transplant recipients was lower (81.2 ml/min) than in the comparison group (97.5 ml/min, p=0.01). After liver transplantation, the renal function worsened in both groups of patients. In a pairwise comparison, the medians of glomerular filtration rate were statistically significantly lower after 12 months, 24 months, 36 months, 48 months after liver transplantation, than before liver transplantation. The median of glomerular filtration rate at the time of immunosuppression conversion was 44.3 ml/min. After the conversion of immunosuppression, the median of glomerular filtration rate gradually increased, and after 36 months the differences in glomerular filtration rate reached statistical significance compared with the level before conversion (69.4 ml/min;p=0.048). These differences still increased after 60 months after conversion (72.3 ml/min; p=0.041).Conclusion. Long-term administration of everolimus with minimization of calcineurin inhibitors exposure with the early conversion to this immunosuppression regime provides a steady improvement in renal function in liver transplant recipients with a low glomerular filtration rate in the preoperative and early post-transplant period.

scholarly journals A Randomized Clinical Trial on Combination Use of Sirolimus and Tacrolimus in Renal Transplant: A De novo Immunosuppression Approach

2020 ◽  
Author(s):  
Farzaneh Hematian ◽  
Nooshin Dalili ◽  
Pedram Ahmadpoor ◽  
Omid Moradi ◽  
Fatemeh Pour-reza-gholi ◽  
...  
Keyword(s):  
Glomerular Filtration Rate ◽  
Filtration Rate ◽  
De Novo ◽  
Immunosuppressive Agents ◽  
Calcineurin Inhibitors ◽  
Transplant Recipients ◽  
Kidney Transplant Recipients ◽  
Long Term Outcomes ◽  
P Values

Abstract Background: With the introduction of new immunosuppressive agents like Sirolimus (SRL), we could increase long term allograft survival and decrease the use of other agents like calcineurin inhibitors. SRL in combination with other immunosuppressive medications like calcineurin inhibitors can lead to increase graft function and produce better long-term outcomes. Methods : We enrolled 40 kidney transplantation recipients in trial and followed them up for a duration of 6 months in Shahid Labbafinejad Medical Center. These patients were assigned to receive Tacrolimus (TAC) in combination with Mycophenolic acid or SRL, along with glucocorticoids. All kidney transplant recipients were followed up for serum creatinine and glomerular filtration rate and also complications during therapy. Results : There were no significant differences between the two treated groups regarding serum creatinine level ( p -values = 0.075). However, glomerular filtration rate was significantly increased in SRL group than the other one ( p -values = 0.023). There was no difference between the number of biopsies performed in the two treated groups. In biopsies that were done, in TAC/Mycophenolic acid group, acute antibody mediated rejection in four patients and in SRL/TAC group, acute cellular rejection in two patients were reported. Total cholesterol level was significantly increased in patients who received SRL ( p -values = 0.002). Other side effects were not significantly different in two arms. Conclusions : Our study demonstrated that SRL in the immunosuppressive regimen of kidney transplant recipients in de novo approach lead to better renal function. The long-term outcomes of de novo SRL utilization in kidney allograft recipients should further be assessed. Trial registration: The trial was retrospectively registered in the Iranian Registry on Clinical Trials ( www.irct.ir , registration code: IRCT20160412027346N6), by the date of 04/30/2019. ( https://www.irct.ir/trial/22416 ) Key words : Kidney transplantation, Immunosuppressive Agents, Mammalian target of rapamycin, Calcineurin Inhibitors, Graft Rejection, Sirolimus, Tacrolimus.

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