Immunosuppression in Liver Transplantation: State of the Art and Future Perspectives

Background: Novel drugs and combinations for immunosuppression (IS) after liver transplantation is one main reason for improved graft and patient survival seen in the last decades. The backbone of IS is still steroids and calcineurin inhibitors, although novel drugs are being introduced, such as the mammalian target of rapamycin inhibitors (mTOR inhibitor). The challenge today, along with increased patient survival, is the adverse effects of long-term use of immunosuppressive drugs, mainly nephrotoxicity and other serious adverse effects. Concepts: The ultimate outcome after liver transplantation would be achieving tolerance, a state where all IS can be withdrawn. In the meantime, different approaches to reduce and withdraw IS have been tested out in different clinical trials with the aim to reduce the adverse effects of steroids and calcineurin inhibitors. This has formed the basis of today’s clinical practice. The different combinations of immunosuppressive drugs have included mTOR inhibitor such as everolimus and different induction drugs such as anti-interleukin 2 receptor antibodies. Regarding induction drugs, lymphocyte depleting (alemtuzumab and ATG) and non-depleting agents, such as basiliximab, have shown advantageous effects. Summary: Alongside steroid and calcineurin inhibitors reduction or elimination, current strategies for post-liver transplantation immunosuppression explore combinations of novel agents. The gauge (or yardstick) here is the fine balance between the adverse effects of IS drugs and the risk of rejection. Long-term maintenance IS regimens, development of tolerance and antibody-mediated rejection are also discussed in this review.

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Renal Dysfunction in Liver Transplantation: The Problem and Preventive Strategies

Canadian Journal of Gastroenterology ◽

10.1155/2004/402743 ◽

2004 ◽

Vol 18 (suppl c) ◽

pp. 27C-40C ◽

Cited By ~ 4

Author(s):

Marcelo Cantarovich

Keyword(s):

Liver Transplantation ◽

Adverse Effects ◽

Renal Dysfunction ◽

Calcineurin Inhibitors ◽

Immunosuppressive Drugs ◽

Therapeutic Monitoring ◽

Wide Range ◽

Nephrotoxic Drugs ◽

Poor Outcomes

Ongoing improvements in survival following liver transplantation have necessitated a re-evaluation of immunosuppression protocols. Corticosteroids and calcineurin inhibitors (CNIs) are the most frequently used immunosuppressive drugs for liver transplantation but are associated with a wide range of adverse effects, such as hypertension, hyperlipidemia and nephrotoxicity. The need for hemodialysis after liver transplantation is associated with poor outcomes. Renal dysfunction in this setting may be caused by pre-existing renal disease, hepatorenal syndrome and/or post-transplant factors, including the use of nephrotoxic drugs, most notably CNIs such as cyclosporine and tacrolimus. The methods that address this problem include the diligent control of metabolic factors (eg, hypertension and hyperlipidemia), therapeutic monitoring of CNIs and withdrawal or reduction of the dosage of CNIs, combined with the use of newer non-nephrotoxic agents. Although there is no clear consensus about the most effective strategy, the optimal long-term immunosuppressive regimen would prevent rejection without causing nephrotoxicity or other significant adverse effects. Recent evidence suggests that the liver is a tolerogenic organ and that some patients may need little, if any, long-term immunosuppression.

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Posttransplant Calcineurin Inhibitors Levels and Intrapatient Variability Are Not Associated With Long-term Outcomes Following Liver Transplantation

Transplantation Journal ◽

10.1097/tp.0000000000002987 ◽

2020 ◽

Vol 104 (6) ◽

pp. 1201-1209

Author(s):

Tommaso Di Maira ◽

Gonzalo Sapisochin ◽

Les Lilly ◽

Victoria Fonés ◽

Marina Berenguer

Keyword(s):

Liver Transplantation ◽

Calcineurin Inhibitors ◽

Long Term Outcomes ◽

Intrapatient Variability

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Treatment of Cyclosporine-Related Adverse Effects by Conversion to Tacrolimus After Liver Transplantation: Long-Term Results

Transplantation Proceedings ◽

10.1016/s0041-1345(98)00298-x ◽

1998 ◽

Vol 30 (4) ◽

pp. 1419-1421 ◽

Cited By ~ 12

Author(s):

J Pratschke ◽

R Neuhaus ◽

S.G Tullius ◽

S Jonas ◽

W.O Bechstein ◽

...

Keyword(s):

Liver Transplantation ◽

Adverse Effects ◽

Long Term Results

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

Journal of Transplantation ◽

10.1155/2014/845438 ◽

2014 ◽

Vol 2014 ◽

pp. 1-45 ◽

Cited By ~ 40

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.

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Steroid induced psychiatric adverse effects: an overview of risk factors, clinical features and management

International Journal of Research in Medical Sciences ◽

10.18203/2320-6012.ijrms20202296 ◽

2020 ◽

Vol 8 (6) ◽

pp. 2365

Author(s):

Anant Parasher ◽

Jeplin Bez

Keyword(s):

Adverse Effects ◽

Steroid Therapy ◽

Wound Repair ◽

Glucocorticoid Receptors ◽

Psychiatric Symptoms ◽

Immunosuppressive Drugs ◽

Psychotic Symptoms ◽

Metabolic Disturbances ◽

Duration Of Treatment

Corticosteroids have been in use since the past five decades as anti-inflammatory and immunosuppressive drugs for the treatment of several pathologies such as asthma, allergy, rheumatoid arthritis, and dermatological disorders. Adverse effects include growth retardation in children, immunosuppression, hypertension, hyperglycemia, inhibition of wound repair, osteoporosis, metabolic disturbances, glaucoma, and cataracts. The psychiatric effects of steroids are due to the wide expression of Glucocorticoid Receptors in the brain, and their long-term modulation can lead to functional and anatomical alterations along with hippocampal dysfunction. In most cases, the psychiatric symptoms disappear on cessation of steroid therapy; others may require some form of therapeutic management. A search was conducted for clinically relevant articles from 1971 to 2016 by including the terms corticosteroids, mania, depression, psychosis and cognitive defects. About one-fifth of patients receiving high doses of corticosteroids develop psychiatric symptoms. These symptoms are observed to be dose-dependent and generally occur during the first few weeks of therapy. Lithium has a preventive as well as therapeutic role, while antipsychotics are reserved for high risk cases with predominant psychotic symptoms. Psychiatric effects of long term steroid therapy have become increasingly common nowadays due to long duration of treatment of many chronic respiratory and orthopedic illnesses. Reduction in the dose or complete discontinuation of steroid therapy has been proven beneficial in many patients. Among the therapeutic options, lithium has a definitive role, both in the prevention as well as treatment of psychiatric symptoms. Better co-ordination between the physician and psychiatrist can go a long way to improve the quality of life in these patients.

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Effect of cyclosporin and tacrolimus on kidney function in liver recipients

Research Results in Pharmacology ◽

10.3897/rrpharmacology.4.29502 ◽

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.

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The Impact of Sirolimus on hepatitis C Recurrence after Liver Transplantation

Canadian Journal of Gastroenterology ◽

10.1155/2011/201019 ◽

2011 ◽

Vol 25 (1) ◽

pp. 28-34 ◽

Cited By ~ 35

Author(s):

Sonal Asthana ◽

Christian Toso ◽

Glenda Meeberg ◽

David L Bigam ◽

Andrew Mason ◽

...

Keyword(s):

Liver Transplantation ◽

Liver Disease ◽

Hepatitis C ◽

Patient Survival ◽

De Novo ◽

Survival Rates ◽

Area Under The Curve ◽

Immunosuppressive Drugs ◽

Initial Recurrence ◽

The Impact

BACKGROUND: While some immunosuppression strategies may accelerate hepatitis C virus (HCV) recurrence after liver transplantation (LT), the impact of sirolimus (SRL) is not known.OBJECTIVE: To assess the risk of biopsy-proven HCV recurrence and patient survival using known and suspected risk factors for HCV recurrence as covariates.METHODS: A retrospective analysis of 141 consecutive patients, including 88 who received de novo SRL therapy, who had undergone a first LT for HCV cirrhosis was conducted. Known and suspected risk factor covariates including transplant era, donor and recipient age, Model for End-stage Liver Disease score, cold ischemia time, immunosuppressive drugs and steroid treatment rejection rates were used in the assessment.RESULTS: Overall, 72.3% of the cohort developed biopsy-proven HCV recurrence. The incidence of HCV recurrence was not significantly different for patients treated with SRL (75% versus 69.8%; P=0.5). There was no difference found for time to recurrence, nor did mean activity or fibrosis scores differ at the time of initial recurrence. However, on follow-up using serial biopsies in patients with recurrence, the mean activity and fibrosis scores were significantly lower in the SRL group. Donor age and acute rejection episodes were the only factors affecting the HCV recurrence rate (expB 1.02 [95% CI 1.01 to 1.03]); P=0.03; and expB 2.8 [95% CI 1.8 to 4.3]; P<0.01], respectively). SRL treatment did not alter patient survival rates. Among patients treated with SRL-based immunosuppression, higher drug area under the curve levels were associated with a trend to lower disease activity and fibrosis at diagnosis; however, higher SRL levels were associated with shorter recurrence-free survival (P=0.038).CONCLUSION: Results of the present analysis suggest that de novo SRL-based immunosuppression can be safely used in patients undergoing LT for HCV-associated liver disease; however, SRL-based immunosuppression did not significantly affect the timing or severity of post-transplant HCV recurrence. HCV recurrence in SRL-treated patients had lower progressive activity and fibrosis levels on serial biopsy.

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Adverse effects of immunosuppressive drugs on long-term graft outcome

Transplantation Proceedings ◽

10.1016/s0041-1345(98)01319-0 ◽

1998 ◽

Vol 30 (8) ◽

pp. 4001-4004 ◽

Cited By ~ 14

Author(s):

L.C Paul

Keyword(s):

Adverse Effects ◽

Immunosuppressive Drugs ◽

Graft Outcome

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Postoperative kidney injury does not decrease survival after liver transplantation

Acta Cirurgica Brasileira ◽

10.1590/s0102-86502012001100010 ◽

2012 ◽

Vol 27 (11) ◽

pp. 802-808 ◽

Cited By ~ 2

Author(s):

Olival Cirilo Lucena da Fonseca-Neto ◽

Luiz Eduardo Correia Miranda ◽

Thales Paulo Batista ◽

Bernardo David Sabat ◽

Paulo Sérgio Vieira de Melo ◽

...

Keyword(s):

Liver Transplantation ◽

Acute Kidney Injury ◽

Orthotopic Liver Transplantation ◽

Multivariate Analyses ◽

Patient Survival ◽

Kidney Injury ◽

Term Survival ◽

Venovenous Bypass

PURPOSE: To explore the effect of acute kidney injury (AKI) on long-term survival after conventional orthotopic liver transplantation (OLT) without venovenous bypass (VVB). METHODS: A retrospective cohort study was carried out on 153 patients with end-stage liver diseases transplanted by the Department of General Surgery and Liver Transplantation of the University of Pernambuco, from August, 1999 to December, 2009. The Kaplan-Meier survival estimates and log-rank test were applied to explore the association between AKI and long-term patient survival, and multivariate analyses were applied to control the effect of other variables. RESULTS: Over the 12.8-year follow-up, 58.8% patients were alive with a median follow-up of 4.5-year. Patient 1-, 2-, 3- and 5-year survival were 74.5%, 70.6%, 67.9% and 60.1%; respectively. Early postoperative mortality was poorer amongst patients who developed AKI (5.4% vs. 20%, p=0.010), but long-term 5-year survival did not significantly differed between groups (51.4% vs. 65.3%; p=0.077). After multivariate analyses, AKI was not significantly related to long-term survival and only the intraoperative transfusion of red blood cells was significantly related to this outcome (non-adjusted Exp[b]=1.072; p=0.045). CONCLUSION: The occurrence of postoperative acute kidney injury did not independently decrease patient survival after orthotopic liver transplantation without venovenous bypass in this data from northeast Brazil.

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