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• W4313887936 abstract "The liver is well known for its immunotolerance, but rejection without immunosuppression is frequently encountered post liver transplantation, especially in humans.1 Indeed, the amount of immunosuppression required post liver transplant is less compared to other organ transplants like kidney, heart, and intestine.2 Reports of successful weaning of immunosuppression have been reported but are not practiced for fear of unwanted alloimmune response leading to rejection. Life-long immunosuppression is needed in most patients for graft survival but is associated with side effects like renal dysfunction, metabolic abnormalities, or risk of de novo malignancies. Also, the appropriate dose of immunosuppression to achieve adequate graft function and prevention of toxicities is very important. One shoe does not fit all. There are significant individual variations in response and side effect profile. Also, the level of immunosuppression varies with the underlying liver disease like autoimmune disease requires higher immunosuppression. Thus, monitoring the adequate immunosuppression with the minimization of drug toxicity is imperative post-transplant. Unfortunately, the current methods for immunosuppression monitoring rely on testing the immunosuppressive drug levels rather than the immune system activity. We have discussed the concept of alloreactivity, available methods of immunosuppression and drug monitoring and investigational methods in this review. The liver is well known for its immunotolerance, but rejection without immunosuppression is frequently encountered post liver transplantation, especially in humans.1 Indeed, the amount of immunosuppression required post liver transplant is less compared to other organ transplants like kidney, heart, and intestine.2 Reports of successful weaning of immunosuppression have been reported but are not practiced for fear of unwanted alloimmune response leading to rejection. Life-long immunosuppression is needed in most patients for graft survival but is associated with side effects like renal dysfunction, metabolic abnormalities, or risk of de novo malignancies. Also, the appropriate dose of immunosuppression to achieve adequate graft function and prevention of toxicities is very important. One shoe does not fit all. There are significant individual variations in response and side effect profile. Also, the level of immunosuppression varies with the underlying liver disease like autoimmune disease requires higher immunosuppression. Thus, monitoring the adequate immunosuppression with the minimization of drug toxicity is imperative post-transplant. Unfortunately, the current methods for immunosuppression monitoring rely on testing the immunosuppressive drug levels rather than the immune system activity. We have discussed the concept of alloreactivity, available methods of immunosuppression and drug monitoring and investigational methods in this review. Alloreactivity refers to the immune response by the receipt of the identification of donor antigen as non-self (alloantigen). This whole immune cascade (if left unchecked) leads to organ rejection. It starts with alloantigen recognition. Alloantigen binds to the host major histocompatibility complex (MHC) peptide on the antigen-presenting cell (APC). MHC-bound alloantigen subsequently binds to the T cell receptor. A number of ligands on the APC bind to T-cell receptors, like CD28, CD154, CD2, CD11a, and CD54 which acts as costimulants leading to T-cell activation. T-cell activation subsequently leads to downstream stimulation of calcineurin. Calcineurin activates nuclear factor of T-cell activation (NFAT). NFAT then translocates into the nucleus and promotes interleukin-2 (IL-2) transcription. IL-2 binds to IL-2 receptors on the T-cell and activates the cell cycle. This results in clonal expansion of the activated T-cells and cell-mediated cytotoxicity. There is the activation of inflammatory milieu due to the secretion of inflammatory cytokines and chemokines and results in graft failure. Immunosuppressants act and inhibit various stages of immune system activation thereby preventing rejection and graft loss.1Lei H. Reinke P. Volk H.-D. Lv Y. Wu R. Mechanisms of immune tolerance in liver transplantation-crosstalk between alloreactive T cells and liver cells with therapeutic prospects.Front Immunol. 2019; 10: 2667Crossref PubMed Scopus (19) Google Scholar,2Londoño M.-C. Rimola A. O'Grady J. Sanchez-Fueyo A. Immunosuppression minimization vs. complete drug withdrawal in liver transplantation.J Hepatol. 2013; 59: 872-879Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar Immunosuppressive agents target various sites of T-cell activation as shown in Figure 1.3Golshayan D. Buhler L. Lechler R.I. Pascual M. From current immunosuppressive strategies to clinical tolerance of allografts.Transpl Int. 2007; 20: 12-24Crossref PubMed Scopus (50) Google Scholar Anti-thymocyte globulin (ATG) inhibits the binding of T-cell receptor with MHC-bound alloantigen and T-cell proliferation. Calcineurin is targeted by cyclosporine and tacrolimus (calcineurin inhibitors [CNIs]). Basiliximab and daclizumab are the monoclonal antibodies that block the IL-2 receptors. Sirolimus and everolimus are the mammalian (mechanistic) target of rapamycin (mTOR) inhibitors that blocks IL-2 receptor-dependent signal transduction. Purine and pyrimidine synthesis inhibitors (azathioprine/mycophenolate mofetil) inhibit DNA synthesis and cell cycle proliferation. Glucocorticoids help in controlling inflammatory cascade. Immunosuppression monitoring post-transplant is imperative to attain a fine balance between adequate immunosuppression and prevention of short- and long-term toxicities related to immunosuppressive drugs. Markers for immune status monitoring are still under development and not available for routine use. At present, drug-level monitoring is used as a surrogate for immunosuppression monitoring. There are significant individual variations in the immune response (at the same drug dosage and levels) that remain a challenge to date.4Zhu A. Leto A. Shaked A. Keating B. Immunologic monitoring to personalize immunosuppression after liver transplant.Gastroenterol Clin N Am. 2018; 47: 281-296Abstract Full Text Full Text PDF PubMed Google Scholar Available modalities for immunosuppression monitoring include drug level monitoring and biomarkers. Biomarkers include immunosuppressive biomarkers, biomarkers for immune response, and biomarkers for organ damage. Drug level monitoring can be done for CNI’s (cyclosporine, tacrolimus), mTOR inhibitors (sirolimus and everolimus), and mycophenolate sodium in view of their narrow therapeutic window.5Langman L. van Gelder T. van Schaik R.H.N. Chapter 5 - pharmacogenomics aspect of immunosuppressant therapy.in: Oellerich M. Dasgupta A. Personalized Immunosuppression in Transplantation [Internet]. Elsevier, San Diego2016https://www.sciencedirect.com/science/article/pii/B9780128008850000059Crossref Scopus (5) Google Scholar Corticosteroids and costimulatory blocker (belatacept) do not need therapeutic monitoring. Drug level monitoring is done using whole blood instead of plasma due to uneven distribution of drug concentration in erythrocytes, plasma and other blood components. The drug levels are concentration and temperature dependant. Mycophenolate sodium is an exception as it is majorly concentrated in the plasma, so is measured in plasma.6Rosano T.G. Effect of hematocrit on cyclosporine (cyclosporin A) in whole blood and plasma of renal-transplant patients.Clin Chem. 1985; 31: 410-412Crossref PubMed Scopus (47) Google Scholar, 7Yatscoff R.W. Wang P. Chan K. Hicks D. Zimmerman J. Rapamycin: distribution, pharmacokinetics, and therapeutic range investigations.Ther Drug Monit. 1995; 17: 666-671Crossref PubMed Scopus (109) Google Scholar, 8Langman L.J. LeGatt D.F. Yatscoff R.W. Blood distribution of mycophenolic acid.Ther Drug Monit. 1994; 16: 602-607Crossref PubMed Scopus (46) Google Scholar Also, immunosuppressive drugs are usually monitored at trough levels except for cyclosporine which is also measured 2 h after the dose (C2 monitoring) (as it has a better correlation with graft rejection).9Nemati E. Einollahi B. Taheri S. et al.Cyclosporine trough (C0) and 2-hour postdose (C2) levels: which one is a predictor of graft loss?.Transplant Proc. 2007; 39: 1223-1224Crossref PubMed Scopus (15) Google Scholar Methods of monitoring therapeutic drug levels include immunoassays and non-immunoassay techniques. The non-immunoassay technique includes liquid chromatography (LC) and mass spectroscopy (MS). Although immunoassays are easy to use and give quick results, LC with MS or tandem MS is considered the gold standard for therapeutic drug level monitoring.10Westley I.S. Taylor P.J. Salm P. Morris R.G. Cloned enzyme donor immunoassay tacrolimus assay compared with high-performance liquid chromatography-tandem mass spectrometry and microparticle enzyme immunoassay in liver and renal transplant recipients.Ther Drug Monit. 2007; 29: 584-591Crossref PubMed Scopus (35) Google Scholar Immunoassays have significant cross-reactivity with the various drug metabolites leading to variable results.11Tempestilli M. Di Stasio E. Basile M.R. et al.Low plasma concentrations of albumin influence the affinity column-mediated immunoassay method for the measurement of tacrolimus in blood during the early period after liver transplantation.Ther Drug Monit. 2013; 35: 96-100Crossref PubMed Scopus (12) Google Scholar,12Strom T. Haschke M. Boyd J. et al.Crossreactivity of isolated everolimus metabolites with the Innofluor Certican immunoassay for therapeutic drug monitoring of everolimus.Ther Drug Monit. 2007; 29: 743-749Crossref PubMed Scopus (25) Google Scholar In LC, the solution of interest is passed through the chromatographic column and separating the components based on physical and chemical properties. Separated components are then passed through the mass spectrometer after ionization. There are certain limitations to this technique. Ions may linger in the collision cell or the ionic charge may get influenced by the spectrometric matrix giving false positive results. Despite these shortcomings, among all available techniques, LC/MS gives the most precise and accurate results.13Vogeser M. Seger C. Pitfalls associated with the use of liquid chromatography-tandem mass spectrometry in the clinical laboratory.Clin Chem. 2010; 56: 1234-1244Crossref PubMed Scopus (245) Google Scholar,14Sallustio B.C. Noll B.D. Morris R.G. Comparison of blood sirolimus, tacrolimus and everolimus concentrations measured by LC-MS/MS, HPLC-UV and immunoassay methods.Clin Biochem. 2011 Feb; 44: 231-236Crossref PubMed Scopus (68) Google Scholar Tacrolimus is the most extensively used immunosuppressant post-transplant. Due to limitations in monitoring the CNI dose with classic pharmacokinetics, an evaluation of the pharmacodynamics has been proposed for drug monitoring. Inhibition of calcineurin phosphatase activity in peripheral blood mononuclear cells (PBMCs) can be used to predict graft function and nephrotoxity.15Fukudo M. Yano I. Masuda S. et al.Pharmacodynamic analysis of tacrolimus and cyclosporine in living-donor liver transplant patients.Clin Pharmacol Ther. 2005; 78: 168-181Crossref PubMed Scopus (72) Google Scholar,16Blanchet B. Duvoux C. Costentin C.E. et al.Pharmacokinetic-pharmacodynamic assessment of tacrolimus in liver-transplant recipients during the early post-transplantation period.Ther Drug Monit. 2008; 30: 412-418Crossref PubMed Scopus (30) Google Scholar Another biomarker for monitoring CNIs is a NFAT lymphocytes. CNIs inhibit calcineurin leading to dephosphorylation of NFAT preventing T cell activation.17Maguire O. Tornatore K.M. O'Loughlin K.L. Venuto R.C. Minderman H. Nuclear translocation of nuclear factor of activated T cells (NFAT) as a quantitative pharmacodynamic parameter for tacrolimus.Cytometry Part J Int Soc Anal Cytol. 2013; 83: 1096-1104Crossref PubMed Scopus (40) Google Scholar Owing to lack of standardization and significant inter-individual variations, further studies are needed for the use of biomarkers.18Noceti O.M. Woillard J.-B. Boumediene A. et al.Tacrolimus pharmacodynamics and pharmacogenetics along the calcineurin pathway in human lymphocytes.Clin Chem. 2014; 60: 1336-1345Crossref PubMed Scopus (15) Google Scholar Analysis of p70s6 kinase and S6 protein phosphorylation is under research for predicting rejection with mTOR inhibitors.19Hartmann B. He X. Keller F. Fischereder M. Guba M. Schmid H. Development of a sensitive phospho-p70 S6 kinase ELISA to quantify mTOR proliferation signal inhibition.Ther Drug Monit. 2013; 35: 233-239Crossref PubMed Scopus (16) Google Scholar,20Dieterlen M.-T. Bittner H.B. Klein S. et al.Assay validation of phosphorylated S6 ribosomal protein for a pharmacodynamic monitoring of mTOR-inhibitors in peripheral human blood.Cytometry B Clin Cytom. 2012; 82: 151-157Crossref PubMed Scopus (32) Google Scholar Inosine monophosphate dehydrogenase I and II in PBMC have been used as a biomarker of Mycophenolic acid (MPA) in various studies. None of these biomarkers are used commercially till date.21Vethe N.T. Bergan S. Determination of inosine monophosphate dehydrogenase activity in human CD4+ cells isolated from whole blood during mycophenolic acid therapy.Ther Drug Monit. 2006; 28: 608-613Crossref PubMed Scopus (22) Google Scholar Genetic polymorphisms in the thiopurine methyltransferase (TPMT) gene are associated with decreased TPMT activity and the development of myelotoxicity because of high TGN metabolite concentrations. Azathioprine is a prodrug that are converted to its active metabolite, thioguanine nucleotides (TGNs). The active metabolites are metabolized by the enzymes TPMT and nudix hydrolase 15 (NUDT15). Genetic polymorphisms in these enzyme genes lead to the decreased enzyme activity and the development of toxicity, especially bone marrow suppression.22Dean L. Azathioprine therapy and TPMT and NUDT15 genotype.in: Pratt V.M. Scott S.A. Pirmohamed M. Medical Genetics Summaries [Internet]. National Center for Biotechnology Information (US), Bethesda (MD)2012http://www.ncbi.nlm.nih.gov/books/NBK100661Google Scholar In the past decade, there have been robust technological advancements in the form of new-generation sequencing and precision medicine. Research work is focusing on the development of genetic tests to identify genetic polymorphism relevant to pharmacokinetics and pharmacodynamics of immunosuppressant drugs.23Almoguera B. Shaked A. Keating B.J. Transplantation genetics: current status and prospects.Am J Transplant Off J Am Soc Transplant Am Soc Transpl Surg. 2014; 14: 764-778Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar CYP3A5, CYP3A4 enzymes metabolizes CNIs and genetic polymorphisms can reduce the drug clearance and lead to nephrotoxicity. CYP3A4 may also influence mTOR inhibitor effects along with decreased cyclosporine and sirolimus clearance.24Moes D.J.A.R. Swen J.J. den Hartigh J. et al.Effect of CYP3A4∗22, CYP3A5∗3, and CYP3A combined genotypes on cyclosporine, everolimus, and tacrolimus pharmacokinetics in renal transplantation.CPT Pharmacometrics Syst Pharmacol. 2014; 3e100Crossref Scopus (63) Google Scholar Adenosine triphosphate-binding cassette subfamily B member 1 (ABCB 1) is an efflux pump which actively excretes xenobiotics into bile ducts. Genetic polymorphism of this pump has been shown to affect the bioavailability of tacrolimus, cyclosporine, and sirolimus.5Langman L. van Gelder T. van Schaik R.H.N. Chapter 5 - pharmacogenomics aspect of immunosuppressant therapy.in: Oellerich M. Dasgupta A. Personalized Immunosuppression in Transplantation [Internet]. Elsevier, San Diego2016https://www.sciencedirect.com/science/article/pii/B9780128008850000059Crossref Scopus (5) Google Scholar Serum bilirubin along with transaminase is the most commonly used test to screen for liver dysfunction. They are closely monitored to assess early liver damage post-transplant. Monitoring graft functions using liver function tests have high sensitivity but are associated with high false positive results as well. Apart from rejection, deranged liver functions can be secondary to biliary obstruction, disease recurrence (AIH (Autoimmune hepatitis), PBC (Primary Biliary cholangitis), PSC (Primary Sclerosing cholangitis)), or infections. Hepatocyte-derived microRNAs, a class of noncoding RNAs, are into active research as surrogate biomarkers for liver injury.25Hu J. Wang Z. Tan C.-J. et al.Plasma microRNA, a potential biomarker for acute rejection after liver transplantation.Transplantation. 2013; 95: 991-999Crossref PubMed Scopus (53) Google Scholar,26Shaked A. Chang B.-L. Barnes M.R. et al.An ectopically expressed serum miRNA signature is prognostic, diagnostic, and biologically related to liver allograft rejection.Hepatol Baltim Md. 2017; 65: 269-280Crossref PubMed Scopus (41) Google Scholar Certain miRNAs are being identified that can predict Acute Cellular Rejection (ACR) and may substitute liver biopsy, the gold standard but invasive method. Liquid biopsy is also finding its way into monitoring graft function post-organ transplant. Early research has shown that quantitative measurement of donor-derived cell-free DNA in plasma is more sensitive in detecting ACR than liver function tests. Cell-free DNA is secreted from the necrotic and apoptotic liver cells that can be detected via dd PCR (droplet digital polymerase chain reaction) assay.27Schütz E. Fischer A. Beck J. et al.Graft-derived cell-free DNA, a noninvasive early rejection and graft damage marker in liver transplantation: a prospective, observational, multicenter cohort study.PLoS Med. 2017 Apr; 14e1002286Crossref Scopus (110) Google Scholar,28Beck J. Bierau S. Balzer S. et al.Digital droplet PCR for rapid quantification of donor DNA in the circulation of transplant recipients as a potential universal biomarker of graft injury.Clin Chem. 2013 Dec; 59: 1732-1741Crossref PubMed Scopus (170) Google Scholar Cytokines are the mediators of immune response and have been studied to understand the immune response post-transplant. Patients with the same drug levels are found to have different levels of cytokines depicting the difference in immune response.29Millán O. Rafael-Valdivia L. Torrademé E. et al.Intracellular IFN-γ and IL-2 expression monitoring as surrogate markers of the risk of acute rejection and personal drug response in de novo liver transplant recipients.Cytokine. 2013; 61: 556-564Crossref PubMed Scopus (61) Google Scholar A study by Kim et al. has shown that combined detection of IL-10, IL-17, and CXCL10 at 1–2 weeks post-operation could predict acute rejection following adult liver transplantation.30Kim N. Yoon Y.-I. Yoo H.J. et al.Combined detection of serum IL-10, IL-17, and CXCL10 predicts acute rejection following adult liver transplantation.Mol Cell. 2016; 39: 639-644Crossref Scopus (17) Google Scholar T lymphocytes play a central role in the cellular-mediated process of rejection. Certain donor-specific T-cells and Tregs (regulatory t-cells) have shown a correlation with the risk of rejection.31He Q. Fan H. Li J.Q. Qi H.Z. Decreased circulating CD4+CD25highFoxp3+ T cells during acute rejection in liver transplant patients.Transplant Proc. 2011; 43: 1696-1700Crossref PubMed Scopus (30) Google Scholar,32Germani G. Rodriguez-Castro K. Russo F.P. et al.Markers of acute rejection and graft acceptance in liver transplantation.World J Gastroenterol WJG. 2015; 21: 1061-1068Crossref PubMed Scopus (41) Google Scholar The immune cell function assay (or ImmuKnow) measures intracellular adenosine triphosphate (ATP) production in T lymphocytes that correlates with T-cell activity. However, there is lacking data on usefulness of ImmunoKnow.33Rodrigo E. Lopez-Hoyos M. Corral M. et al.ImmuKnow as a diagnostic tool for predicting infection and acute rejection in adult liver transplant recipients: a systematic review and meta-analysis [Internet].in: Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews. Centre for Reviews and Dissemination (UK), 2012https://www.ncbi.nlm.nih.gov/books/NBK115946Crossref Scopus (64) Google Scholar Immunosuppressive drugs can be categorized according to their mechanism of action in the following classes.•Polyclonal and monoclonal antibodies against T lymphocyte cell surface antigens•Corticosteroids•Calcineurin inhibitors (cyclosporine and tacrolimus)•mTOR inhibitors (sirolimus and everolimus)•Antimetabolites (azathioprine, mycophenolate mofetil, and mycophenolate sodium) ATG—It is a polyclonal antibody that leads to the depletion of circulating T-cells by binding them followed by opsonization and macrophage phagocytosis. ATG is not routinely used in liver transplantation. But it has been used for the induction of immunosuppression in patients with pre-transplantation renal dysfunction where CNIs are not preferred. It has also been used for the treatment of steroid-resistant rejection. Monoclonal antibodies used in liver transplantation are directed against IL-2 receptors preventing T-cell proliferation. Humanized monoclonal antibodies include basiliximab (Simulect) and daclizumab (Zenapax) whereas muromonab-CD3 (OKT3) is a murine monoclonal antibody. OKT3 is no longer used as it is highly immunogenic and less tolerated as compared to chimeric humanized antibodies. Both basiliximab and daclizumab have a comparable efficacy but daclizumab was removed from the market due to several reports of inflammatory brain disorders. Basiliximab is widely used in steroid-resistant rejection along with CNIs or as CNI sparing agent. Serum drug levels of antibodies are not monitored but the optimal dose for ATG (and possibly Basiliximab) is often monitored using total lymphocyte counts or more specifically CD3+ T cells.34Ata P. Kara M. Özdemir E. et al.Monitoring of CD3(+) T-cell count in patients receiving antithymocyte globulin induction after cadaveric renal transplantation.Transplant Proc. 2013; 45: 929-931Crossref PubMed Scopus (5) Google Scholar Glucocorticoids suppress the antibody and compliment binding along with the suppression of T-cells. They are used for the induction phase and treatment of acute cellular rejection. Due to long-term side effects of steroids, early weaning with early introduction of other immunosuppression is advocated. Generally, high-dose glucocorticoids are given in the perioperative phase (500 or 1000 mg of methylprednisolone) and are tapered over the first week to 10–20 mg of prednisolone equivalent and stopped at 3–6 months. There is no available assay to measure serum levels of glucocorticoids. In general, the trend is toward the lower usage of steroids post-liver transplant. CNIs used post-transplant are cyclosporine and tacrolimus. Although cyclosporine was the first-line immunosuppressant till mid-1990s, subsequently was largely replaced by tacrolimus. Tacrolimus was found to have superior graft function and survival and was better tolerated but is more commonly associated with post-transplant diabetes mellitus and neurotoxicity. Cyclosporine levels in the blood should be frequently monitored, initially daily and then less frequently when graft function stabilizes. The therapeutic trough levels of cyclosporin for proper graft function in the first week are 300–350 ng/ml and then reduced subsequently to 200–300 ng/ml by 1 month and 100–200 ng/ml after 3 months. Levels of <100 ng/ml are usually tolerated after 1 year. Tacrolimus is started at low doses (0.5–1 mg twice daily) as early as possible post-transplantation. The target trough levels of Tacrolimus are 6–9 ng/ml for the first week followed by 5–8 ng/ml for 1 month. Subsequently, lower doses of tacrolimus are acceptable to maintain a stable graft function. In patients with underlying renal dysfunction, lower doses of CNIs administered with the addition of either mycophenolate mofetil (MMF) or monoclonal antibody.35Lake J. Patel D. David K. Richwine J. Morris J. The association between MMF and risk of progressive renal dysfunction and death in adult liver transplant recipients with HCV.Clin Transplant. 2009; 23: 108-115Crossref PubMed Scopus (6) Google Scholar,36Neuberger J.M. Mamelok R.D. Neuhaus P. et al.Delayed introduction of reduced-dose tacrolimus, and renal function in liver transplantation: the “ReSpECT” study.Am J Transplant Off J Am Soc Transplant Am Soc Transpl Surg. 2009; 9: 327-336Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar In patients with underlying alcoholic liver disease or hemochromatosis generally tolerate low doses of CNIs, higher doses of CNIs with higher target trough levels are desirable in some situations like autoimmune liver diseases. Special caution is needed for patients on directly acting anti-virals (DAA) for HCV-related liver disease. Some of the DAAs increase CNI metabolism by the effects on CYP 3A4, therefore, drug levels should be closely monitored.37Bixby A.L. Fitzgerald L. Leek R. Mellinger J. Sharma P. Tischer S. Impact of direct-acting antivirals for hepatitis C virus therapy on tacrolimus dosing in liver transplant recipients.Transpl Infect Dis Off J Transplant Soc. 2019; 21e13078Google Scholar Sirolimus is a macrolide antibiotic produced by Streptomyces hygroscopicus. It has shown to be an effective immunosuppressant but is not used in the first-line due to its side effects. The risk of the development of hepatic artery thrombosis in the post-transplant phase has limited its use. Food and drug administration recommends against its use in the first 30 days of transplant for the same. Sirolimus may be considered in situation with CNI intolerance like renal dysfunction or neurotoxicity. A metanalysis had shown non-significant improvement in renal function in liver transplant (LT) recipients with renal insufficiency when switched from CNIs to sirolimus. Also, it was associated with more side effects and drug discontinuation.38Asrani S.K. Leise M.D. West C.P. et al.Use of sirolimus in liver transplant recipients with renal insufficiency: a systematic review and meta-analysis.Hepatol Baltim Md. 2010; 52: 1360-1370Crossref PubMed Scopus (55) Google Scholar Common side effects are pancytopenia, edema, hyperlipidemia, and oral ulcers. Although rare, acute respiratory distress syndrome is a lethal complication associated with sirolimus. Drug level monitoring is available for sirolimus, although the use of sirolimus is decreasing in liver transplant patients after the advent of everolimus (see below). It is a hydroxyethyl derivative of sirolimus with higher bioavailability and shorter half-life than sirolimus. With a shorter half-life and favorable side effect profile, it has largely replaced sirolmus as the preferred mTOR inhibitor. With a starting dose of 0.75 mg twice daily, target trough level of 3–8 ng/mL are considered optimal when used in combination with CNIs. In CNI-free regimens, the trough level target should be 6–9 ng/mL.39Shipkova M. Hesselink D.A. Holt D.W. et al.Therapeutic drug monitoring of everolimus: a consensus report.Ther Drug Monit. 2016; 38: 143-169Crossref PubMed Scopus (82) Google Scholar Antimetabolite drugs used in liver transplantation are MMF and azathioprine. In most cases, MMF is the preferred antimetabolite except in pregnancy where azathioprine is considered safe.40Germani G. Pleguezuelo M. Villamil F. et al.Azathioprine in liver transplantation: a reevaluation of its use and a comparison with mycophenolate mofetil.Am J Transplant Off J Am Soc Transplant Am Soc Transpl Surg. 2009; 9: 1725-1731Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar Both are the prodrugs of MPA produced from fungus Penicillium. MPA inhibits inosine monophosphate dehydrogenase thus preventing the formation of guanosine monophosphate and cell replication. In contrast to most body cells, lymphocytes lack purine salvage pathway. MMF is started in doses of 500 mg twice daily and then increased to 1 g twice daily. Mycophenolate sodium is started at the dose of 360 mg twice daily and is increased to 720 mg twice daily. Side effects are less and mainly include bone marrow suppression and gastrointestinal tract upset. They have an advantage over CNI as they lack neurotoxicity and nephrotoxicity. CNI dose can be reduced and early steroid withdrawal can be done with the addition of MMF. RCT comparing long-term CNI with MMF monotherapy has shown a better renal profile with the MMF group but with increased frequency of acute rejection.41Schmeding M. Kiessling A. Neuhaus R. et al.Mycophenolate mofetil monotherapy in liver transplantation: 5-year follow-up of a prospective randomized trial.Transplantation. 2011; 92: 923-929Crossref PubMed Scopus (36) Google Scholar Assays to measure MMF have been developed but are not available commercially (simply because these are rarely used in view of low drug toxicity).. It is a prodrug of 6-mercaptopurine that inhibit purine synthesis leading to reduced replication of T and B cells. Azathioprine is given at a dose of 1.5–2.0 mg/kg daily with a maximum dose of 200 mg daily. Assessing TPMT metabolite enzyme activity and measuring levels of 6-TG can help optimize the dosing of azathioprine. Side effects include gastrointestinal tract disturbances, bone marrow suppression, pancreatitis, hepatotoxicity, and lymphoma. Common drug interaction of immunosuppressants is due to the metabolism of CNI's and mTOR inhibitors by CYP3A enzymes as mentioned in Table 1.Table 1Common Drug Interactions in Patients on Immunosuppression.Common types of drug interactionsCommon Examples▪Inhibitor of CYP3A metabolism and/or P-gp efflux▪Increase CNIs/mTOR inhibitors levels▪Amiodarone▪ART-boosting agents (e.g. ritonavir, cobicistat)▪Azole antifungals (e.g. fluconazole)▪Diltiazem▪HIV protease inhibitors▪Macrolide antibiotics▪Induction CYP3A metabolism and/or P-gp efflux pumping▪Decrease CNIs/mTOR inhibitors levels▪Antiepileptics (e.g. carbamazepine, phenytoin, phenobarbital, primidone)▪Rifamycins (e.g. rifabutin, rifampin, rifapentine)CNIs: calcineurin inhibitors, mTOR: mammalian (mechanistic) target of rapamycin Open table in a new tab CNIs: calcineurin inhibitors, mTOR: mammalian (mechanistic) target of rapamycin Coadministration of nephrotoxic drugs like aminoglycosides, non steroidal anti-inflammatory drugs (NSAIDs) or amphotericin B with CNIs may potentiate renal dysfunction and thus be avoided or carefully monitored. Coadministration of potassium-sparing diuretics like amiloride/spironolactone, angiotensin converting enzyme (ACE) inhibitors/ARBs or trimethoprim-sulfamethoxazole with CNIs may cause severe hyperkalemia. Coadministration of cyclosporine with sirolimus can increase sirolimus concentrations. Administration of sirolimus from cyclosporine must have a gap of at least 4 h. Coadministration of statins drugs with cyclosporine can increase statin levels and risk of myotoxicity and hence avoided. Tacrolimus is preferred over cyclosporine in patients on statins. Pravastatin and fluvastatin have less interactions and are preferred. Immunosuppressive therapy should be continued around the surgery. Potential drug interaction between antibiotics and immunosuppressants must be taken care of. As there is an increased risk of nephrotoxicity with intravenous CNIs, they are replaced with intravenous corticosteroids during the perioperative period. Post-liver transplant pregnancies are high-risk pregnancies due to the increased risk of fetal and maternal complications like hypertension, preeclampsia, and pre-term delivery.42Deshpande N.A. James N.T. Kucirka L.M. et al.Pregnancy outcomes of liver transplant recipients: a systematic review and meta-analysis.Liver Transplant Off Publ Am Assoc Study Liver Dis Int Liver Transplant Soc. 2012; 18: 621-629Crossref PubMed Scopus (108) Google Scholar Avoidance of conception with proper use of contraception is advocated for at least 1 year post-transplantation. Balanced immunosuppression is needed to avoid complications related to immunosuppression with the prevention of rejection. Corticosteroids are considered safe and can be continued if already taken, though there is an increased risk of gestational diabetes and hypertension. CNIs should be continued as pre-pregnancy state. MMF is teratogenic and should be stopped at least 6 weeks before conception and can be replaced with azathioprine.43Christopher V. Al-Chalabi T. Richardson P.D. et al.Pregnancy outcome after liver transplantation: a single-center experience of 71 pregnancies in 45 recipients.Liver Transplant Off Publ Am Assoc Study Liver Dis Int Liver Transplant Soc. 2006; 12: 1138-1143Crossref PubMed Scopus (127) Google Scholar There is insufficient data on the safety of mTOR inhibitors in pregnancy. Immunosuppression monitoring is very important post-transplant to balance the risk of rejection and short- and long-term side effects of the immunosuppressants. Any individual needs a personalized immunosuppression regimen. MMF should be avoided during pregnancy. At present, drug level monitoring along with close monitoring of liver functions and vigilance for side effects is practiced. Biomarkers are under development and may change future practice with better-individualized immunosuppression monitoring. Manav Wadhawan - conceptualisation, review of literature & editing. Charu Gupta - review of literature, original draft. None." @default.
• W4313887936 created "2023-01-10" @default.
• W4313887936 creator A5059641658 @default.
• W4313887936 creator A5088172214 @default.
• W4313887936 date "2023-07-01" @default.
• W4313887936 modified "2023-09-29" @default.
• W4313887936 title "Immunosuppression Monitoring—What Clinician Needs to Know?" @default.
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