mTORi in Immunosuppression after Liver Transplantation: Comparison
View Latest Version
Please note this is a comparison between Version 2 by Catherine Yang and Version 1 by Letizia Todeschini.

Hepatocellular carcinoma (HCC) is the most common malignancy of the liver and the third cause of cancer-related mortality. Liver transplantation is a treatment option for nonresectable patients with early-stage HCC, with more significant advantages when Milan criteria are fulfilled. mTOR inhibitors (mTORi) have been introduced as an alternative immunosuppressive approach to conventional conventional calcineurin inhibitors (CNIs)-based regimens to address both immunosuppression and cancer control. The PI3K-AKT-mTOR signalling pathway regulates protein translation, cell growth, and metabolism, and the pathway is frequently deregulated in human tumours.

  • hepatocellular carcinoma
  • HCC
  • immunosuppression
  • liver transplantation
  • mTOR

1. Introduction

Given the mTOR pathway’s role in cellular survival and replication, its inhibition with rapamycin and rapalogs has been established as an immunosuppression option in patients undergoing solid organ transplantation. mTOR inhibitors reduce the risk of graft rejection, thus providing a better outcome for LT recipients. While liver transplantation has provided a new chance for selected patients with HCC, this option has been burdened by a high mortality rate, which in patients treated with azathioprine reached a value of approximately 70% at 1 year [84][1]. These dramatic results were mitigated by implementing a stricter patient selection and introducing a CNIs-based immunosuppressive regimen. Notably, the latter led to a drastic reduction in the mortality rate, settling at a little over 20% [84][1]. Cyclosporine and tacrolimus are the drugs of choice in the early treatment of LT recipients, thanks to their ability to block T-cell activation and migration [85][2]. Both tacrolimus and cyclosporine inhibit calcineurin, a cytoplasmic protein responsible for IL2 gene expression, and reduce the production of chemotactic factors involved in lymphocyte recruitment [85][2]. Utilizing CNIs gave obvious benefits in post-LT management, but their nephrotoxicity and high risk of recurrence required reduced CNI-exposure treatment [29,56,57,86][3][4][5][6]. In the last 20 years, a growing interest has been developed in mTOR inhibitors, as an immunosuppressive effect was reported in both in vitro and in vivo assessments [87][7]. This effect is achieved thanks to the ability of rapamycin and its derivatives to induce T-cells anergy while promoting an allograft tolerance through increasing Tregs levels to the detriment of other CD4+ cell subpopulations [13][8]. mTOR inhibitors also exhibit an antiproliferative effect, making it an optimal option in managing LT recipients with an HCC as an indication, particularly when the Milan criteria were fulfilled [88][9].

2. Immunosuppressive Regimens

Recipients receive an immunosuppressive regimen after LT to reduce allograft rejection probability. CNIs (cyclosporine and tacrolimus), glucocorticoids, and mycophenolate mofetil are the drugs of choice in the settings of initial combined therapy. When stability in liver function is obtained, monotherapy is advised, usually CNIs-based. Because of their nephrotoxic side effects, CNIs reduction or discontinuation is recommended in the long term [88][9]. In HCC patients, mTOR inhibitors are an appropriate option to achieve this purpose, and their beneficial effects are discussed. As of today, a conversion to mTORi-based therapy is advised within 3 months from LT, with the possibility to administer these drugs in monotherapy or in combination with reduced CNIs [88][9]. Care must be taken when everolimus is the drug of choice for tacrolimus reduction, as a target range of 3 ng/mL should be achieved before the reduction of the CNI [78][10].
Other therapeutic combinations have been explored other than mTOR inhibitors with reduced-CNIs. Co-administration of mTORi with mycophenolate (MPA) is one of the possible options, as it improves renal function and quality of life 24 months after liver transplantation compared with standard CNI with MPA immunosuppression [27][11].

3. Impact on Renal Function

Nephrotoxicity is a well-established adverse effect of the long-term utilization of CNIs. Endothelial dysfunction and vasoconstriction play an essential role in CNIs renal damage, which can be traced back to ROS production, RAS activation, and induction of imbalances in vasodilators and vasoconstrictors production [89][12]. Renal damage becomes one of the most essential complications in transplanted patients, accounting for increased morbidity and mortality [90][13]. Indeed, renal dysfunction is the main indication for discontinuing CNIs, and mTORi are optimal alternatives thanks to their renoprotective effect. However, given that both sirolimus and everolimus serve this scope, other studies are needed to determine which drugs are more effective in achieving a long-term renoprotective effect [91][14].

3.1. Sirolimus

A significant improvement in renal function was found when SRL was administered to transplanted HCC patients who developed nephrotoxicity after a first course of CNIs. This effect was mainly present in patients that started the sirolimus regimen within 3 months from LT. In these recipients, eGFR increased from 30 mL/min to 57 mL/min [16][15]. Similar results may be achieved when low doses of sirolimus are administered along with reduced tacrolimus. Significantly fewer patients had a CKD grade ≥3 at 6 months when low sirolimus + low tacrolimus was chosen over a conventional tacrolimus regimen [31][16].
Conflicting results came from a meta-analysis conducted by Asrani et al., who found that the beneficial effect on renal function after conversion to sirolimus was non-significant [92][17]. However, this result may be explained by selection bias and late conversion (>6 months) to the sirolimus regimen. Evaluation of patients treated with sirolimus showed they had the most impaired renal function baseline compared to controls. Moreover, sirolimus was believed to be administered later than needed in patients with preserved renal function, promoting its degeneration in this window period [92][17]. When conversion from CNIs to sirolimus is needed, an early switch is recommended as it gives greater possibilities for renal function recovery. Retrospective evaluation of renal function in patients undergoing early (within 3 months) or late conversion from CNIs demonstrated significantly higher eGFR mean values at all time points in the first group [15][18].

3.2. Everolimus

An everolimus-based regimen preserves and, in some cases, improves renal function [93][19]. In the H2304 study, a significant difference of 8.5 mL/min/1.73 m2 (p < 0.001) was found in eGFR values at any point from week 6 post-LT in patients treated with everolimus plus reduced tacrolimus over controls treated with tacrolimus alone [18][20]. Even when a complete conversion was chosen over a reduction of the previous CNI-based regimen, a statistically significant increase in GFR values was noted in patients treated with an everolimus [19][21]. When an everolimus + mycophenolate regimen was chosen for CNIs conversion, a statistically significant improvement in eGFR was achieved at both 12 (88.01 vs. 60.63 mL/min/1.73 m2, p = 0.020) and 24 (87.37 vs. 53.29 mL/min/1.73 m2, p = 0.013) months compared to the CNI arm [27][11]. As described for sirolimus, a better outcome in renal function can be achieved when conversion to an everolimus-based regimen occurs sooner. Indeed, in LT recipients with eGFR <60 mL/min/1.73 m2, a more substantial improvement in renal function at 36 months was achieved when an early conversion (within 12 months) was chosen (55% if conversion within 3 months, 39.4% if conversion at 4–12 months, 20.9% if conversion was after 12 months) [24][22].

4. Impact on Graft Rejection

With the introduction of immunosuppressive therapy after LT, the rate of acute cellular rejection (ACR) and chronic rejection (CR) has reduced to 15–25% and 3–17%, respectively [94][23]. When mTORi are used in LT recipients, no difference can be found in acute graft rejection rate compared to a CNI-based regimen (RR 1.1, 95%, CI 0.94–1.28) [65][24]. This non-inferiority in preventing graft rejection has been proven for both sirolimus and everolimus and can be ascribed to mTORi suppressive action on the immune system [20,30,92,95][17][25][26][27]. Mainly, rapamycin and its derivatives promote the expansion of Treg at the expense of other CD4+ subgroups by altering APCs activity and T cells polarization, thus favoring immunological tolerance against the graft [13,59,96][8][28][29]. APCs’ activity is also affected by the inhibition of the mTOR pathway. It has to be mentioned that CD8+ T cells are preserved, accounting for the added benefit of granting an immunological response to viral infections that may occur in this period of immunodeficiency.
While a clear benefit can be described when mTORi is used to convert from a CNIs regimen, a de novo administration has not shown to be an advantage in acute graft rejection rate compared to CNIs [97,98][30][31]. This evidence may be explained by the fact that, compared to CNIs, mTORi are not equally capable of interfering with the acute expression of inflammatory cytokines. A CNI-based induction course followed by a mTORi-based regimen is thus advisable [99][32]. Moreover, a reduction rather than withdrawal of CNI is recommended, as evaluation of tacrolimus elimination in LT recipients has shown a higher rejection rate at 1 year (19.9%) compared to everolimus plus reduced tacrolimus (3.7%, and even tacrolimus controls (10.7%) [18][20].

References

  1. Starzl, T.E.; Iwatsuki, S.; Shaw, B.W.; Gordon, R.D.; Esquivel, C. Liver Transplantation in the Ciclosporin Era. Prog. Allergy 1986, 38, 366–394.
  2. Komolmit, P.; Davies, M.H. Tacrolimus in liver transplantation. Expert Opin. Investig. Drugs 1999, 8, 1239–1254.
  3. Rodríguez-Perálvarez, M.; Colmenero, J.; González, A.; Gastaca, M.; Curell, A.; Caballero-Marcos, A.; Sánchez-Martínez, A.; Maira, T.D.; Herrero, J.I.; Almohalla, C.; et al. Cumulative exposure to tacrolimus and incidence of cancer after liver transplantation. Am. J. Transplant. 2022, 22, 1671–1682.
  4. Hoffman, D.; Mehta, N. Recurrence of hepatocellular carcinoma following liver transplantation. Expert Rev. Gastroenterol. Hepatol. 2021, 15, 91–102.
  5. Duvoux, C.; Toso, C. mTOR inhibitor therapy: Does it prevent HCC recurrence after liver transplantation? Transplant. Rev. 2015, 29, 168–174.
  6. Mihatsch, M.J.; Kyo, M.; Morozumi, K.; Yamaguchi, Y.; Nickeleit, V.; Ryffel, B. The side-effects of ciclosporine-A and tacrolimus. Clin. Nephrol. 1998, 49, 356–363.
  7. Schuler, W.; Sedrani, R.; Cottens, S.; Häberlin, B.; Schulz, M.; Schuurman, H.-J.; Zenke, G.; Zerwes, H.-G.; Schreier, M.H. SDZ RAD, A NEW RAPAMYCIN DERIVATIVE: Pharmacological Properties In Vitro and In Vivo. Transplantation 1997, 64, 36.
  8. Ghazal, K.; Stenard, F.; Dahlqvist, G.; Barjon, C.; Aoudjehane, L.; Scatton, O.; Conti, F. Treatment with mTOR inhibitors after liver transplantation enables a sustained increase in regulatory T-cells while preserving their suppressive capacity. Clin. Res. Hepatol. Gastroenterol. 2018, 42, 237–244.
  9. Cillo, U.; De Carlis, L.; Del Gaudio, M.; De Simone, P.; Fagiuoli, S.; Lupo, F.; Tisone, G.; Volpes, R. Immunosuppressive regimens for adult liver transplant recipients in real-life practice: Consensus recommendations from an Italian Working Group. Hepatol. Int. 2020, 14, 930–943.
  10. De Simone, P.; Fagiuoli, S.; Cescon, M.; De Carlis, L.; Tisone, G.; Volpes, R.; Cillo, U.; Panel, C. Use of Everolimus in Liver Transplantation: Recommendations From a Working Group. Transplantation 2017, 101, 239.
  11. Kadry, Z.; Stine, J.G.; Dohi, T.; Jain, A.; Robyak, K.L.; Kwon, O.; Hamilton, C.J.; Janicki, P.; Riley, T.R.I.; Butt, F.; et al. Renal Protective Effect of Everolimus in Liver Transplantation: A Prospective Randomized Open-Label Trial. Transplant. Direct 2021, 7, e709.
  12. Naesens, M.; Kuypers, D.R.J.; Sarwal, M. Calcineurin Inhibitor Nephrotoxicity. Clin. J. Am. Soc. Nephrol. 2009, 4, 481.
  13. Trinh, E.; Alam, A.; Tchervenkov, J.; Cantarovich, M. Impact of acute kidney injury following liver transplantation on long-term outcomes. Clin. Transplant. 2017, 31, e12863.
  14. Tsai, K.-F.; Li, L.-C.; Hsu, C.-N.; Lin, C.-C.; Lin, Y.-H.; Cheng, Y.-F.; Wang, C.-C.; Chen, C.-L. Effects of Conversion from Calcineurin Inhibitors to Sirolimus or Everolimus on Renal Function and Possible Mechanisms in Liver Transplant Recipients. J. Clin. Pharmacol. 2019, 59, 326–334.
  15. Vivarelli, M.; Dazzi, A.; Cucchetti, A.; Gasbarrini, A.; Zanello, M.; Di Gioia, P.; Bianchi, G.; Tamè, M.R.; Gaudio, M.D.; Ravaioli, M.; et al. Sirolimus in Liver Transplant Recipients: A Large Single-Center Experience. Transplant. Proc. 2010, 42, 2579–2584.
  16. Mulder, M.B.; van Hoek, B.; van den Berg, A.P.; Polak, W.G.; Alwayn, I.P.J.; de Jong, K.P.; de Winter, B.C.M.; Verhey-Hart, E.; Erler, N.S.; den Hoed, C.M.; et al. Three-year results of renal function in liver transplant recipients on low-dose sirolimus and tacrolimus: A multicenter, randomized, controlled trial. Liver Transplant. 2023, 29, 184.
  17. Asrani, S.K.; Leise, M.D.; West, C.P.; Murad, M.H.; Pedersen, R.A.; Erwin, P.J.; Tian, J.; Wiesner, R.H.; Kim, W.R. Use of Sirolimus in Liver Transplant Recipients with Renal Insufficiency: Systematic Review and Meta-Analysis. Hepatology 2010, 52, 1360–1370.
  18. Rogers, C.C.; Johnson, S.R.; Mandelbrot, D.A.; Pavlakis, M.; Horwedel, T.; Karp, S.J.; Egbuna, O.; Rodrigue, J.R.; Chudzinski, R.E.; Goldfarb-Rumyantzev, A.S.; et al. Timing of sirolimus conversion influences recovery of renal function in liver transplant recipients. Clin. Transplant. 2009, 23, 887–896.
  19. Tedesco-Silva, H.; Saliba, F.; Barten, M.J.; De Simone, P.; Potena, L.; Gottlieb, J.; Gawai, A.; Bernhardt, P.; Pascual, J. An overview of the efficacy and safety of everolimus in adult solid organ transplant recipients. Transplant. Rev. 2022, 36, 100655.
  20. De Simone, P.; Nevens, F.; De Carlis, L.; Metselaar, H.J.; Beckebaum, S.; Saliba, F.; Jonas, S.; Sudan, D.; Fung, J.; Fischer, L.; et al. Everolimus with Reduced Tacrolimus Improves Renal Function in De Novo Liver Transplant Recipients: A Randomized Controlled Trial. Am. J. Transplant. 2012, 12, 3008–3020.
  21. Fischer, L.; Klempnauer, J.; Beckebaum, S.; Metselaar, H.J.; Neuhaus, P.; Schemmer, P.; Settmacher, U.; Heyne, N.; Clavien, P.-A.; Muehlbacher, F.; et al. A Randomized, Controlled Study to Assess the Conversion From Calcineurin-Inhibitors to Everolimus after Liver Transplantation—PROTECT. Am. J. Transplant. 2012, 12, 1855–1865.
  22. Saliba, F.; Dharancy, S.; Salamé, E.; Conti, F.; Eyraud, D.; Radenne, S.; Antonini, T.; Guillaud, O.; Guguenheim, J.; Neau-Cransac, M.; et al. Time to Conversion to an Everolimus-Based Regimen: Renal Outcomes in Liver Transplant Recipients from the EVEROLIVER Registry. Liver Transplant. 2020, 26, 1465.
  23. Choudhary, N.S.; Saigal, S.; Bansal, R.K.; Saraf, N.; Gautam, D.; Soin, A.S. Acute and Chronic Rejection after Liver Transplantation: What A Clinician Needs to Know. J. Clin. Exp. Hepatol. 2017, 7, 358–366.
  24. Grigg, S.E.; Sarri, G.L.; Gow, P.J.; Yeomans, N.D. Systematic review with meta-analysis: Sirolimus- or everolimus-based immunosuppression following liver transplantation for hepatocellular carcinoma. Aliment. Pharmacol. Ther. 2019, 49, 1260–1273.
  25. Ferreiro, A.O.; Vazquez-Millán, M.A.; López, F.S.; Gutiérrez, M.G.; Diaz, S.P.; Patiño, M.J.L. Everolimus-Based Immunosuppression in Patients with Hepatocellular Carcinoma at High Risk of Recurrence after Liver Transplantation: A Case Series. Transplant. Proc. 2014, 46, 3496–3501.
  26. Sapisochin, G.; Lee, W.C.; Joo, D.J.; Joh, J.-W.; Hata, K.; Soin, A.S.; Veldandi, U.K.; Kaneko, S.; Meier, M.; Leclair, D.; et al. Long-Term Effects of Everolimus-Facilitated Tacrolimus Reduction in Living-Donor Liver Transplant Recipients with Hepatocellular Carcinoma. Ann. Transplant. 2022, 27, e937988-1.
  27. Jeng, L.-B.; Lee, S.G.; Soin, A.S.; Lee, W.-C.; Suh, K.-S.; Joo, D.J.; Uemoto, S.; Joh, J.; Yoshizumi, T.; Yang, H.-R.; et al. Efficacy and safety of everolimus with reduced tacrolimus in living-donor liver transplant recipients: 12-month results of a randomized multicenter study. Am. J. Transplant. 2018, 18, 1435–1446.
  28. Thomas Decaens, F.; oise Roudot-Thoraval, S.B.-H.; bastien Dharancy, O.C.; Res, D.C. Role of immunosuppression and tumor differentiation in predicting recurrence after liver transplantation for hepatocellular carcinoma: A multicenter study of 412 patients. World J. Gastroenterol. 2006, 12, 7319–7325.
  29. Battaglia, M.; Stabilini, A.; Roncarolo, M.-G. Rapamycin selectively expands CD4+CD25+FoxP3+ regulatory T cells. Blood 2005, 105, 4743–4748.
  30. De Simone, P.; Metselaar, H.J.; Fischer, L.; Dumortier, J.; Boudjema, K.; Hardwigsen, J.; Rostaing, L.; De Carlis, L.; Saliba, F.; Nevens, F. Conversion from a calcineurin inhibitor to everolimus therapy in maintenance liver transplant recipients: A prospective, randomized, multicenter trial. Liver Transplant. 2009, 15, 1262–1269.
  31. Mártinez, J.M.A.; Pulido, L.B.; Bellido, C.B.; Usero, D.D.; Aguilar, L.T.; Moreno, J.L.G.; Artacho, G.S.; Díez-Canedo, J.S.; Gómez, L.M.M.; Bravo, M.Á.G. Rescue Immunosuppression with Mammalian Target of Rapamycin Inhibitor Drugs in Liver Transplantation. Transplant. Proc. 2010, 42, 641–643.
  32. Powell, J.D.; Pollizzi, K.N.; Heikamp, E.B.; Horton, M.R. Regulation of Immune Responses by mTOR. Annu. Rev. Immunol. 2012, 30, 39–68.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)
Video Production Service
Feedback