Modification of immunosuppressive therapy as risk factor for complications after liver transplantation

Abstract

Management of complications post-liver transplantation (LT) includes immunosuppressive manipulations with the aim to reduce the overall burden of immunologic suppression and compensate for renal, cardiovascular, metabolic toxicities, and for the increased oncologic risk. Two approaches can be implemented to reduce immunosuppression-related adverse events: upfront schedules tailored to the pretransplant individual patient's risk profile versus downstream modifications in the event of immunosuppression-related complications. Upfront strategies are supported by evidence originating from prospective randomized trials and consist of triple/quadruple schedules whereby calcineurin inhibitors (CNI)-exposure is reduced with combination of anti-CD25 monoclonal antibodies, antimetabolites and corticosteroids. Quadruple regimens allow for staggering of CNI introduction and higher renal function in the early term, but their superiority in the long term has not yet been established. A more recent upfront schedule contemplates early (4 weeks) introduction of mammalian target of rapamycin inhibitor (mTORi) everolimus and allows for reduction of CNI up to 4 years posttransplantation. Incorporation of mTORi has the potential to prolong time to recurrence for patients with hepatocellular carcinoma. However, as suggested by the available evidence, downstream immunosuppressive manipulations are more frequently adopted in clinical practice. These encompass CNI replacement and immunosuppression withdrawal. Switching CNI to mTORi monotherapy is the option most commonly adopted to relieve renal function and compensate for posttransplant malignancies. Its impact is dependent on interval from transplantation and underlying severity of renal impairment. Introduction of mTORi is associated with longer overall survival for patients with extrahepatic posttransplant malignancies, but results are awaited for recurrences of hepatocellular carcinoma. Immunosuppression withdrawal seems feasible (70%) in very long term survivors (>10 years), but is not associated with reversal of immunosuppression-related complications. Awaiting novel immunosuppressive drug categories, integration of upfront strategies with the aim to reduce CNI-exposure and a low threshold for adjustment in the posttransplant course are both advisable to improve long-term outcomes of LT.

Introduction

Immunosuppression plays a key role in achieving favorable outcomes after liver transplantation (LT), but is also the source of significant morbidity. Introduction of calcineurin inhibitors (CNI), cyclosporine (CsA) and tacrolimus (TAC), has resulted in considerable advancements with reduction of acute rejection (AR) rates and improvements in short-term graft survival [1], [2]. With current CNI-based schedules, the risk of posttransplant AR is estimated between 5% and 20% within 1 year after surgery, while 1-year graft survival exceeds 85–90% in most international registries [3]. However, improvements in short-term outcomes have not been mirrored by long-term results [3].

Whilst early posttransplant morbidities consist of complications related to surgery, infections and poor graft quality, extrahepatic morbidities contribute to graft attrition rates in the long term, and arise from renal, cardiovascular, and metabolic toxicities produced by CNIs [4], [5], [6], [7], [8]. In recipients surviving more than 1 year, malignancies account for 22% of deaths, while renal insufficiency is strongly associated with increased overall mortality (HR: 4.10, 95%CI: 2.87–5.86; P<0.001) [9]. In times when most liver grafts are allocated on a patient basis, as per the model for end-stage liver disease (MELD) scoring system, the goal of current immunosuppressive schedules is twofold: to maintain long-term efficacy and reduce CNI-related toxicities [10].

Over the last decade, much has been done in the experimental and clinical setting to mitigate toxicities associated with use of CsA and TAC and tailor immunosuppression to the individual patient's clinical risk. Most immunosuppression schedules currently include antimetabolites (mycophenolic acid (MPA) derivatives) or less frequently induction agents (anti-CD25 monoclonal antibodies) [11]. The association of TAC and mycophenolate mofetil (MMF) currently represents 75% of initial immunosuppressive regimens, and use of MMF is reported in about 45% of maintenance patients at 1 and 2 years after transplantation [10]. Reduction of CNI exposure with addition of MMF is associated with comparable efficacy and lessened cardiovascular and renal toxicities versus standard-exposure schedules [8], [12], while ab initio CNI-free regimens are limitedly implemented in clinical practice due to a higher risk of treatment failure [13].

Incorporation of mammalian target of rapamycin (mTOR) inhibitors, everolimus (EVR) and sirolimus (SIR), in reduced-exposure CNI-based schedules is a further approach to address the issues related to long-term patient and graft survival. mTORi and CNIs act on different sites of the T-cell activation pathway [14]. EVR and SIR are selective inhibitors of the mTOR complex, which is a serine–threonine kinase with a key role for cell metabolism and functions [14]. Over the last decade, mTORi have received substantial attention, since they are associated with a more favorable renal profile versus CNIs and have shown anti-proliferative properties in experimental and clinical studies, with a potential for reduction of recurrent or de novo posttransplant malignancies [15], [16].

Tailoring of immunosuppressive schedules has a definite role in improving the results of LT and is the most common strategy to harness short-term and long-term immunosuppression-related adverse events (AE) [10]. To that regard, two approaches can be implemented in clinical practice in: upfront strategies, whereby an immunosuppressive regimen is delivered based on pretransplant and/or intraoperative risk factors versus downstream policies, these latter consisting of adjustments in the presence of AEs (Table 1). The current paper reviews the available literature with the aim of defining the immunosuppressive strategies which might contribute to reduce the posttransplant attrition rates, especially in regards to the toxicities associated with use of CNIs.