Post-Kidney Transplant Measures to Prevent Rejection: History
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Please note this is an old version of this entry, which may differ significantly from the current revision.
Contributor:
Divyanshu Malhotra
,
Priyanka Jethwani

With increasing knowledge of immunologic factors and with the advent of potent immunosuppressive agents, the last several decades have seen significantly improved allograft survival. Today, median graft survival ranges from 11.7 years in deceased donor kidney transplants up to 19.2 years in living donor kidney transplants. However, despite overall improved short to medium-term allograft survival, long-term allograft outcomes remain unsatisfactory.

  • preventing rejection
  • HLA matching
  • immunosuppression
  • biomarkers
  • emerging therapies

1. Prevention of Cell Mediated Rejection

T-cell proliferation and signaling pathways

The key cellular mediator of rejection is the T-lymphocyte. Most immunosuppressive agents work by disrupting the keys pathways of T-cell activation. Signal 1 is initiated by the interaction of the T-cell receptor (TCR) on the T-cell with the Major Histocompatibility Complex (MHC) molecule on the Antigen Presenting Cell (APC) via the CD3 complex. Co-stimulation or Signal 2 constitutes the interaction of CD80 and CD86(B7) on the surface of APC and CD28 on T-cells. Both Signal 1 and 2 are essential to activate three signal transduction pathways: the calcium-calcineurin pathway, the RAS-mitogen activated protein (MAP) kinase pathway and the nuclear factor-kb pathway [1]. These pathways activate transcription factors that trigger the expression of many new molecules, including interlekin-2 (IL-2), CD154 and CD25. IL-2 and other cytokines activate the “target of rapamycin” pathway to provide Signal 3, the trigger for cell proliferation. Nucleotide synthesis is also required for lymphocyte proliferation and the mobilization of effector T-cells. Different classes of immunosuppressive agents target different steps of the T-cell proliferation pathways to prevent their activation and subsequent rejection of the allograft. These mechanisms have been explained in more detail in another article in this series titled Pathophysiology of rejection in kidney transplantation.
CNIs are considered the backbone of maintenance immunosuppression and are used by a vast majority of transplant centers in the United States [2] Cyclosporine and tacrolimus are the two agents of this class in clinical use and voclosporin remains an investigational agent currently [3]. CNIs bind to their binding proteins (FKBP for tacrolimus and cyclophilin for cyclosporine) and inhibit calcineurin. This inhibition blocks the dephosphorylation and activation of nuclear factor NFAT thus preventing transcription of IL-2 which is critical to lymphocyte proliferation. Cyclosporine was touted as a gamechanger after its discovery in the 1980s. However, it has largely been replaced by tacrolimus as the CNI of choice in most immunosuppression regimens. A large meta-analysis of 30 trials (4102 patients) comparing these two agents favored tacrolimus for multiple endpoints with a 44% reduction in death-censored graft failure and 31% reduction in the risk of acute rejection within 1 year of transplant [4]. This analysis also revealed a significantly higher risk of development of insulin-dependent diabetes, neurological and GI side effects with tacrolimus. Given the side effect profile and varying sensitivity to the two drugs, an individualized approach in deciding a CNI may be needed in certain patients.
Antimetabolites are an integral part of maintenance immunosuppression regimens. The most used agents are Mycophenolic acid (MPA) and azathioprine. These agents inhibit nucleotide synthesis which limits T and B-lymphocyte proliferation. MPA was approved by the FDA for the prevention of rejection in 1995. This was based on the Tricontinental Study (North America, Europe and Australia) which showed a significantly lower risk of acute rejection in kidney transplant recipients on MPA compared to Azathioprine [5]. A meta-analysis of 23 studies which included 3301 participants showed the MPA was superior to azathioprine in terms of the risk of graft loss including death (RR 0.82), death-censored graft loss (RR 0.78) and any acute rejection (RR 0.65) [6]. Thus, MPA has become the favored agent in combination with CNIs in most patients for the prevention of acute rejection. It is contra-indicated in pregnancy as it is teratogenic.

Calcineurin Inhibitor Free Regimens

Although tacrolimus remains the main component of maintenance immunosuppression, it is associated with significant toxicities and thus may not be usable in all patients. In such situations, CNI free regimens have been established. Belatacept is a first in class co-stimulation blocker which interacts with Signal 2 and thus selectively blocks T-cell activation. It was approved by FDA in 2011 based on two landmark trials which compared Belatacept with cyclosporine for maintenance immunosuppression both in standard and extended criteria kidneys. Although the rate of acute rejection was higher in the Belatacept cohorts, however, this did not have an impact on long term patient and graft survival [7][8]. Subsequent meta-analysis of 5 studies that compared Belatacept and CNIs (1535 patients) have reported similar rates of death, allograft survival and acute rejection after 3 years of transplant [9]. Studies of conversion from CNI to Belatacept have also shown similar trends [10]. mTOR inhibitors engage FKBP12 to create complexes that inhibit the target of rapamycin which blocks Signal 3 by preventing cytokine receptors from activating the cell cycle. mTOR inhibitors have been evaluated in several regimens but have not shown to be superior to either CNIs or antimetabolites in prevention of rejection. However, they do have anti-viral and anti-tumor activity and thus are favored in such situations [11].
Corticosteroids remain an integral part of most immunosuppressive regimens. They inhibit production of activating cytokines and downregulate the expression of activating molecules on the surface of T-lymphocytes. However, recent trends have seen an increase in steroid free regimens to minimize long term side effects [2].

2. Prevention of Antibody Mediated Rejection

Antibody-mediated rejection (AMR) is a significant complication following kidney transplantation that contributes toward both short- and long-term injury in approximately 1% to 10% of kidney transplant recipients [12]. Certain factors including allo-sensitization, patient non-compliance and iatrogenic reduction in immunosuppression contribute significantly to the emergence of de novo HLA and non-HLA antibodies or persistence of pre-existing antibodies. This increases risk for chronic AMR which is thought to be a significant cause of premature graft failure [13][14][15]. The best treatment for AMR is to prevent it. Post-transplant prevention of AMR should involve a multipronged strategy.
Maintenance of immunosuppression remains a key element in this approach. Therapeutic tacrolimus levels are associated with reduced production of de novo DSA [16]. CNI minimization strategies have been proposed and used to mitigate the potential side effects of CNIs including nephrotoxicity which was thought to contribute significantly to late allograft loss. However, given the extensive research to suggest that chronic AMR is the bigger culprit [13][14][15], care providers must be careful when making changes to immunosuppression regimens, including lowering targets for CNI troughs and weighing the potential risks/benefits, especially in highly sensitized transplant patients. Mycophenolate Mofetil (MMF) is associated with decreased formation of de novo DSA and rates of biopsy proven AMR as compared to no MMF/Azathioprine in combination with a CNI [6][17]. Belatacept has also been shown to lower the incidence of donor specific antibody (DSA) formation both when used de novo and when used as a CNI conversion strategy [7][8][18]. Belatacept-based immunosuppression decreases pre-existing antibodies [19]. Thus, careful curation of immunosuppression strategies considering demographic variables, immunological risk and patient preferences should be made to minimize the risk of AMR and prevention of premature graft loss.
Another aspect of this multipronged strategy involves monitoring for the development of DSA. Currently there are no standard guidelines for this approach, and individual centers create their own protocols based on multiple factors including patient variables, HLA lab and logistical support and cost. It is debatable if lab monitoring for alloantibodies is needed in all transplant patients, but it seems justified in immunologically high-risk patients, desensitized recipients, patients with a suspicion for rejection and during treatment of an AMR to recognize allograft injury early and prevent its translation into chronic rejection [20].

3. Minimizing Non-Compliance

Non-compliance is a major risk factor for rejection and has been associated with premature graft loss [21][22]. It encompasses multiple aspects of transplant related care including immunosuppression medication, lab monitoring, transportation to medical visits and lifestyle modifications to minimize the risk of non-immunological graft injury and subsequent failure. Certain demographic groups are considered high risk including teenagers and young adults who are transitioning from the pediatric to adult renal services, certain social and ethnic groups and individuals known to be facing financial crises that make drugs and ongoing medical care unaffordable [22]. Given the seriousness and potential graft threatening consequences of non-adherence, every effort should be made to address this early as the likely benefits of this intervention will be diminished after emergence of de novo DSA [23]. Enhanced surveillance, especially for higher risk groups, may include interviews including additional use of telemedicine, visits from social workers, utilizing the transplant pharmacy teams to monitor prescription filling records and reiterating medication education and additional antibody screening at regular intervals especially for higher immunological risk patients.

4. Treatment of Rejection

Patients at risk for denovo DSA formation have preceding cellular rejections with more intense inflammation within the microvasculature and if not treated early and aggressively, it is postulated that peritubular capillaritis can lead to increased HLA expression in the microcirculation, thereby increasing the risk of allo-recognition by the recipient B-cell compartment. Moreover, when cellular rejection coincides with DSA and antibody-mediated microvascular injury, it may accelerate the time to graft dysfunction and graft loss [21]. This underscores the importance of aggressive treatment for active cellular or antibody mediated rejection to decrease the risk of chronic rejection and graft loss [21]. After addressing the acute inflammatory component with appropriate intervention, the treating physician should make sure to optimize the maintenance immunosuppression. This may include resetting target troughs for CNIs, especially if a CNI minimization strategy has been previously employed for the patient, re-introduction or increase in antimetabolite or consideration of switch to Belatacept if CNI avoidance is warranted. Treatment strategies, including details of medications used, for the same are outlined in another article of this series titled Current therapies in Kidney Transplant Rejection.

5. Role of Biomarkers

A multitude of novel biomarkers have been developed to assess allograft health and predict rejection before changes in GFR take place and to predict long term graft outcomes. Only a few are currently available in clinic practice. A potential early indicator for the injury and loss of allograft is donor derived cell free DNA circulating in the blood of transplanted patients. This is measured as a percent of recipient circulating DNA and increase in this fraction is a sensitive marker of allograft injury [24]. Three assays, based on NGS technology: Allosure, TRAC and Prospera are currently available for commercial use. These have been validated and are most useful for detection of AMR [25][26]. Gene expression profiling based non-invasive test available as TRUGRAF is validated for detecting subclinical rejection [27]. These tests can potentially be used for monitoring allograft function post rejection treatment and can direct immunosuppression therapy changes to balance the risk of future rejection and adverse effects. One major hindrance to their consistent use is the associated cost and thus the companies offering these tests should work towards subsidizing them over time. Other promising biomarker classes which can potentially contribute to the prevention of both acute and chronic rejection include chemokines, free microRNAs and leucocyte subclasses [28].

6. Emerging Therapies

Given the significant improvements in acute cellular rejection rates over time [2], there have not been any major efforts to make newer drugs affecting T-lymphocyte signaling. Novartis launched the CIRRUS-1 study in 2018 to evaluate the safety and efficacy of iscalimab (a non-B-lymphocyte depleting anti CD-40 monoclonal antibody) in kidney transplant recipients [29]. However, this was terminated early due to an interim analysis showing inferiority to tacrolimus-based regimens for rejection prevention. Clazakizumab, a monoclonal antibody against the IL-6 ligand has shown promising results in a phase 2 pilot RCT [30]. It decreased the DSA levels in patients with AMR after 1 year of transplant and showed a significantly slower decline in GFR as compared to placebo. A large phase 3 trial of clazakizumab in patients with chronic active AMR is currently ongoing [31]. Tocilizumab, a monoclonal antibody against the IL-6 receptor has shown promise both in desensitization protocols as well as for treatment of chronic AMR [32][33]. Larger RCTs are needed to confirm these findings and justify the use given significant cost associated with this drug.
Daratumumab is a monoclonal antibody against CD38 which has shown promising results in decreasing anti-HLA antibodies in AMR [34][35] and has been proposed as an agent for desensitization and treatment of AMR. However, more concrete evidence is needed before its acceptance in clinical practice.
Belimumab is a humanized, monoclonal, anti B-lymphocyte stimulator (BLyS) IgG1 antibody that prevents B-cell survival and differentiation into plasma cells. In a RCT with 28 kidney transplant recipients, there was no significant difference in the risk of major infections compared to standard immunosuppression but the IL-10/IL6 ratio of the B-cell distribution was skewed towards a regulatory profile and activated memory B-cells and plasmablasts were significantly reduced [36] This likely has the downstream effect of decreasing the risk of rejection. However, specific studies are needed to address this.
Imlifidase, an IgG degrading enzyme of Streptococcus pyogenes (IdeS), cleaves human IgG at a specific amino acid sequence within the hinge region producing Fc and F(ab)s fragments effectively blocking complement dependent cytotoxicity and antibody dependent cellular cytotoxicity [37]. It was associated with rapid reduction and even elimination of DSA [38][39]. However, rebound in DSA and anti-IdeS antibody development are significant issues associated with its use. This, along with the patient population that it will benefit the most will need to be addressed in future studies.
Berinert and Cinryze are plasma C1-esterase inhibitors that have been tested in two pilot studies and have shown a functional improvement in AMR [40][41]. More trials are currently underway and hopefully will define the role of these agents in the prevention of AMR.
Key points of the post-transplant measures
  • Maintenance immunosuppression is a key part of preventing acute and chronic rejection and should be individualized and offer different mechanisms and less side effects.
  • Strategies should be devised to increase long-term compliance.
  • Acute rejections should be treated aggressively to decrease risk of chronic rejection.
  • Novel biomarkers should be utilized in a judicious manner.
  • Emerging therapies offer promise but need more studies.

This entry is adapted from the peer-reviewed paper 10.3390/jcm12185938

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