Long-term use of calcineurin inhibitors (CNIs) has been linked to nephrotoxicity and renal impairment. The current goals of immunosuppressive schedules are to maintain long-term efficacy, but also to reduce CNI-related toxicities (De Simone et al., 2017b). The addition of agents such as mycophenolate mofetil and the mTOR inhibitors have enabled the development of CNI-sparing regimens that maintain immunosuppression while lowering cardiovascular and renal toxicities compared with standard CNI regimens.
To achieve optimal immunosuppression while minimising adverse events, it is necessary to tailor the immunosuppressive schedule to the individual patient. This has typically been achieved using one of two strategies (De Simone et al., 2017b):
The development of upfront strategies is based on evidence from prospective randomised trials outlining triple or quadruple schedules that reduce CNI exposure through addition of induction therapy, antimetabolites, mTOR inhibitors and corticosteroids. However, the optimal choice of immunosuppressive regimen in upfront strategies is still uncertain. For instance, while the benefits of CNI elimination appears clear, in practice this has proven difficult and increased risks of acute rejection have been observed. Meanwhile, reducing the exposure of CNI has been achieved with triple and quadruple immunosuppressive regimens, but consensus is still lacking on what therapies are optimal for this role. While quadruple strategies allow for staggering of CNI introduction and short-term improvements in renal function, their long-term superiority over triple therapy regimens remains uncertain. Meanwhile, early addition of everolimus (4 weeks) offers the possibility of long-term reduction in CNI exposure and even the potential for CNI tapering and withdrawal (De Simone et al., 2017b).
Table 8: Upfront immunosuppressive strategies to minimise CNI-related adverse events (De Simone et al., 2017b)
Downstream immunosuppressive modifications are more frequently implemented in clinical practice than upfront strategies and typically involve CNI replacement and immunosuppression withdrawal. The goal of these manipulations is typically to reduce the overall immunosuppressive burden, restore some immune function or to address treatment-related toxicities.
Complete withdrawal of immunosuppression offers the opportunity to spare treatment-related toxicities and adverse events, but questions remain over its feasibility, safety and identification of candidates. The best predictor of withdrawal tolerance after liver transplantation appears to be time. Nearly 80% of patients who had survived over 10 years post transplant were able to successfully withdraw. However, this dropped to 0% in patients less than 6 years after liver transplantation and who were under 49 years of age. Meanwhile, the benefits of withdrawal remain unclear with little improvement in CNI-related side effects, possibly due to the long period of exposure required before withdrawal is possible (De Simone et al., 2017b).
The replacement of CNI has been demonstrated with conversion of patients to monotherapy with a mTOR inhibitor. No head-to-head studies are available for MMF and mTOR inhibitor monotherapy, but data suggest that mTOR inhibitor monotherapy can be achieved at a shorter interval since transplantation that MMF monotherapy. MMF monotherapy was typically performed in recipients >3 years after transplantation and about 75% of patients achieve an absence of acute rejection with success principally dependent on time since transplantation, lower baseline CNI exposure and lower frequency of tacrolimus use. The success of mTOR inhibitor was also largely dependent on time since transplantation but the risk of acute rejection appears to be less than 10% (De Simone et al., 2017b).
Indications for late conversion to everolimus with CNI minimisation may include chronic allographic nephropathy, CNI nephrotoxicity and CNI arteriolopathy. Furthermore, cancer is one of the main indications for late conversion to everolimus. In the open-label, multicentre APOLLO study, adjusted eGFR within the on-treatment population was significantly higher at 12 months after conversion in the everolimus-continuation group versus the CNI-continuation group, with a mean post-transplantation period of 7 years before conversion. Other studies have shown that patients, without adverse events and already with satisfactory renal function, had favourable graft function with everolimus late-induction with CNI elimination or reduction (Uchida et al., 2018a).
Older patients, aged more than 55 years, may be more likely to have frequent adverse effects and therapy discontinuations (Uchida et al., 2018b). The study compared patients who continued taking everolimus after late conversion from antimetabolites to those patients who discontinued everolimus after late conversion. Patients in the everolimus-discontinuation group were significantly older (57.9 +/- 12.0 years) than those in the everolimus-continuation group (45.7+/- 11.2 years) (p=0.062) and age at conversion significantly correlated with everolimus discontinuation (p=0.12).
Development and the application of non-invasive biomarkers able to predict the likelihood of graft rejection would limit the need for invasive biopsies (Khan et al., 2016). There has been significant recent progress in the identification of biomarkers for immune tolerance in renal and liver transplantation that would limit, or eradicate, the use of immunosuppression (Mastoridis et al., 2016).
A set of 13 genes was identified that were independently predictive for the development of fibrosis at 1 year in kidney transplant recipients. The predictive value of the gene set was validated on an independent cohort from the Genomics of Chronic Allograft Rejection (GoCAR) study (n=45) and two independent, publicly available expression datasets (n=306) (O'Connell et al., 2016).
Exosomes are a subset of extracellular vesicles, which are increasingly recognised for their role in various diseases and their potential for therapeutic use. Exosomes expressing self-antigens (Sags) and donor human leucocyte antigens (HLAs) have been detected in the circulation following lung, heart, kidney and islet cell transplantation. A study by Sharma et al. (2019) analysed circulating exosomes from patients who had undergone lung (n=30), heart (n=8), or kidney (n=15) transplantation. The exosomes were found to contain tissue-associated self-antigens (SAgs), collagen V (Col-V) and K-alpha 1 tubulin (Kα1T), heart SAgs, myosin and vimentin, and kidney SAgs, fibronectin and collagen IV (Col-IV). The study also reported that:
The study’s findings suggest that circulating exosomes with tissue-associated SAgs have the potential to be a non-invasive biomarker to monitor allograft status after transplantation.
A non-invasive biomarker might ultimately replace the need for an invasive biopsy to prove rejection (Mirzakhani et al., 2019). In addition, exosomes may also have a role in monitoring immunosuppression to help guide decisions on the reduction of dosage or even the cessation of treatment due to severe side-effects. Furthermore, there is the role of donor-derived exosomes in contributing to allograft dysfunction and failure.
Ravichandran et al. (2019) found that circulating exosomes in lung transplant recipients with acute or chronic rejection mostly originated from donor lung tissue. Circulating exosomes (carrying allo-antigens, lung SAgs, micro-RNAs, proteasome, co-stimulatory molecules and pro-inflammatory transcription factors) provide an efficient process for antigen presentation by direct, semi-direct and indirect pathways, and the subsequent triggering of the immune response to allo-antigens and lung Sags. The latter have been implicated in the pathogenesis of chronic lung allograft dysfunction (CLAD).
About two-thirds of deaths after the first year following liver transplantation are unrelated to graft dysfunction. The causes need to be addressed to improve long-term outcomes and include obesity and metabolic syndrome, hepatitis C infection, and malignancy, with malignancy having a distinctive spectrum in liver transplant recipients. Regular screening should be carried out for metabolic syndrome and malignancies. In addition, the minimum degree of immunosuppression required to achieve optimal allograft function requires continued research (Bhat et al., 2014; Charlton, 2014).