Immunosuppression in adult liver transplant recipients: a 2024 update from the Italian Liver Transplant Working Group

Abstract

Purpose: Advances in surgical procedures and immunosuppressive therapies have considerably improved the outcomes of patients who have undergone liver transplantation in the past few decades. In 2020, the Italian Liver Transplant Working Group published practice-oriented algorithms for immunosuppressive therapy (IT) in adult liver transplant (LT) recipients. Due to the rapidly evolving LT field, regular updates to the recommendations are required. This review presents a consensus- and evidence-based update of the 2020 recommendations.

Methods: The Italian Liver Transplant Working Group set out to address new IT issues, which were discussed based on supporting literature and the specialists' personal experiences. The panel deliberated on and graded each statement before consensus was reached.

Results: A series of consensus statements were formulated and finalized on: (i) oncologic indications for LT; (ii) management of chronic LT rejection; (iii) combined liver-kidney transplantation; (iv) immunosuppression for transplantation with an organ donated after circulatory death; (v) transplantation in the presence of frailty and sarcopenia; and (vi) ABO blood group incompatibility between donor and recipient. Algorithms were updated in the following LT groups: standard patients, critical patients, oncology patients, patients with specific etiology, and patients at high immunologic risk. A steroid-free approach was generally recommended, except for patients with autoimmune liver disease and those at high immunologic risk.

Conclusion: The updated consensus- and evidence-based 2024 recommendations for immunosuppression regimens in adult patients with ABO-compatible LT address a range of clinical variables that should be considered to optimize the choice of the immunosuppression treatment in clinical practice in Italy.

Keywords: Calcineurin; Hepatocellular cancer; Immunosuppression; Liver metastasis; Liver transplantation; Nephrotoxicity; Recurrence; Rejection; mTOR inhibitor.

Fig. 1

Algorithm for immunosuppressive therapy in critical patients undergoing liver transplantation (as defined in Supplementary methods). Induction is indicated to allow delayed calcineurin (CNI) introduction, early CNI minimization, and a steroid-free approach. Critical patients with an infection contracted after the transplantation should be considered for reduction/discontinuation of immunosuppressive therapy. The indicated target blood levels of immunosuppressants are not binding. In these patients, induction therapy with basiliximab to delay the introduction of CNIs by a few days is recommended. CNI reduction with the introduction of mycophenolate mofetil or everolimus is also recommended, while CNI monotherapy should be avoided. In critical patients with CNI-related neurotoxicity and/or nephrotoxicity a CNI-free regimen with everolimus in monotherapy or combined with mycophenolate mofetil is recommended, following induction therapy. A CNI-free regimen based on everolimus with or without mycophenolate mofetil may eventually be considered, with some caution, for patients receiving other regimens within this protocol, especially at > 3 months post-transplantation. BMI body mass index, CsA cyclosporine, CP critical patient, d delayed, DCD donated after circulatory death, eGFR estimated glomerular filtration rate, EVR everolimus, ICU intensive care unit, IND induction, MDRO multidrug-resistant organism, MELD-Na model for end-stage liver disease-sodium, MMF mycophenolate mofetil, MONO monotherapy, NASH non-alcoholic steatohepatitis, NCEP-ATP III National Cholesterol Education Program: Adult Treatment Panel III, NKDOQI National Kidney Disease Outcomes Quality Initiative, SBP spontaneous bacterial peritonitis, SPPB Short Physical Performance Battery, TAC tacrolimus

Fig. 2

Algorithm for immunosuppressive therapy in oncology patients undergoing liver transplantation. The indicated target blood levels of immunosuppressants are not binding. A protocol of CNI reduction with everolimus is recommended. While CNI-containing and CNI-free regimens were both recommended in the 2020 version of the algorithm for patients with HCC, [5], a CNI-free regimen with everolimus monotherapy is the preferred option in the updated algorithm, especially in patients with high-risk or recurrent oncologic disease, owing to the antiproliferative properties of mTOR inhibitors. ^aIntrahepatic cholangiocarcinoma, perihilar cholangiocarcinoma, hepatoblastoma, and liver metastases of NET, GIST, or colorectal cancer. ^bFor patients with HCC or NET. CNI calcineurin inhibitor, CsA cyclosporine, d delayed, EVR everolimus, GIST, gastrointestinal stromal tumor, HCC hepatocellular carcinoma, IND induction, mTOR mammalian target of rapamycin, MONO monotherapy, NET neuroendocrine tumor, NMSC non-melanoma skin cancer, PTLD post-transplant lymphoproliferative disorder, TAC tacrolimus

Fig. 3

Algorithm for immunosuppressive therapy in patients with specific etiology undergoing liver transplantation. The indicated target blood levels of immunosuppressants are not binding. Patients requiring liver–kidney transplantation should be treated according to the protocol for critical patients or standard patients, depending on the patient clinical status and after evaluation by a multidisciplinary team [5]. The immunosuppressive protocol for patients with AILD is the same as that recommended for standard patients with the addition of corticosteroids at a dose that should be adjusted based on efficacy and reported adverse events at 0–3 months and > 3 months post-transplantation. AILD autoimmune liver disease, CNI calcineurin inhibitor, CsA cyclosporine, EVR everolimus, MMF mycophenolate mofetil, PLD polycystic liver disease, TAC tacrolimus

Fig. 4

Algorithm for immunosuppressive therapy in patients at high immunologic risk undergoing liver transplantation. The indicated target blood levels of immunosuppressants are not binding. Patients with chronic graft rejection should first receive induction therapy (basiliximab) plus corticosteroids followed by tacrolimus in monotherapy plus corticosteroids for patients with compliance problems, or CNI-reducing regimens with tacrolimus and mycophenolate mofetil or everolimus, plus corticosteroids in both cases. In ABO-I patients, transplant surgery can be urgent or elective. Candidates for elective surgery should be desensitized with cycles of plasmapheresis/plasma exchange with or without immunoglobulins to reach an anti-ABO titer < 1:64. Patients needing an emergency intervention should be conditioned preoperatively with one cycle of plasmapheresis/plasma exchange. Following conditioning, the immunosuppression protocols for emergency and elective liver transplants are similar and involve induction therapy plus corticosteroids followed by tacrolimus–mycophenolate mofetil with corticosteroids. Monitoring of anti-ABO titer is recommended; if the titer is > 1:64, second-line immunomodulatory treatment involves cycles of plasmapheresis/plasma exchange with or without immunoglobulins. If the ABO titer continues to be > 1:64, third-line treatment is recommended with use of anti-CD20 agents or proteosome inhibitors. At > 3 months post-transplantation, the recommended regimens remain the same as during the 3 months following the intervention, with a decrease in the tacrolimus dose. ^aOrgan from a living donor. ^bFrequency and duration of PAF/PE depend on anti-A and anti-B titers. ^cThe use of polyclonal antibodies (ALG, ALT) requires monitoring and caution due to the high risk of infections and related complications. ^dRepeat weekly during the first month. ^eRecommended dose (may vary depending on individual center protocols). Adjustments of immunosuppressive therapy should be made based on patient clinical characteristics. 2L second line, 3L third line, ABO-I ABO incompatible, ALG antilymphocyte globulin, ALT alanine aminotransferase, CNI calcineurin inhibitor, EVR everolimus, IVIG intravenous immunoglobulin, MMF mycophenolate mofetil, MONO monotherapy, PAF plasmapheresis, PE plasma exchange, TAC tacrolimus