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Tuesday 25 June 2019
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Immunosuppression in kidney transplantation

Anna Carollo, Alessio Provenzani and Piera Polidori
Clinical Pharmacy Service,
Istituto Mediterraneo Trapianti e Terapie Alta Specializzazione (ISMETT), Palermo, Italy

There have been numerous advances in solid organ transplantation since its clinical inception in the 1950s. In the case of kidney transplantation, the improvement in short-term allograft survival rates has been particularly impressive, with one-year graft survival exceeding 90% in transplantation centres. Long-term graft survival rates now show some evidence of improvement, with those cadaveric transplants performed in 1988 having a renal allograft survival half-life of eight years, increasing to a half-life of 12 years for those performed in 1994. The major cause of late allograft loss is slow deterioration of allograft function with increasing fibrosis, termed chronic rejection. While early surgical success made organ transplantation possible in the 1950s, the breakthrough in clinical organ transplantation was achieved through the discovery and invention of modern immunosuppressive agents in the early to mid 1980s. Current forms of immunosuppression are ineffective in the prevention of chronic rejection. Moreover, the potency of the newer agents has been associated with life-threatening complications.

Management of potential complications in renal allograft recipients is complex and requires meticulous care and attention. The investigation and management of graft dysfunction is critically dependent on the time of onset. There are two stages of organ dysfunction: early and late.

Early graft dysfunction
Early graft dysfunction occurs anywhere from the first few hours to few months after transplantation and, generally, the earlier the onset of dysfunction, the greater the promptness required to assess and correct the problem.
In this early stage, acute rejection is one of the most common causes of transplant failure and there can be four types: hyperacute, acute cellular rejection, acute humoral rejection, and early subclinical rejection.

Physiology of rejection
The rejection process consists of two stages: the  stage in which the recipient’s T-cells recognise the donor’s alloantigens and therefore become active and proliferate, and the  stage in which rejection occurs.

In the stage, alloantigens activate both CD4+ T-cells and CD8+ T-cells. In the effector stage, the CD4+ cells activated during the stage (Th1) produce the cytokines involved in the cell-mediated reaction. More precisely, they produce interleukin 2 (IL-2), which promotes the proliferation of T-cells, CD4+ and CD8+, the interferon gamma (IFN-γ) that causes the cytotoxic reaction (mediated by cytolytic T lymphocytes (CTL) cells, such as cytotoxic T-cells), the delayed hypersensitivity (mediated by macrophages) and, finally, tumour necrosis factor beta (TNF-β), which has a direct cytotoxic effect on transplanted cells.5 Therefore successful kidney transplantation requires donor/recipient HLA and ABO compatibility, and long-term immunosuppression therapy. In fact, the success of kidney transplantation has improved over the last decade largely because of new immunosuppressive agents, which have decreased the incidence and severity of acute cellular rejection. The adverse effects of immunosuppressive agents is essential to improving long-term survival.

Treatment
Today, kidney transplantation has excellent short-term outcomes, with a decrease in episodes of acute rejection. However, improvement in long-term allograft survival has been much less impressive over the last few decades. Thus, the goal of current immunosuppressive therapies is to maintain a balance between reduction of acute rejection episodes and
organ-specific and systemic side effects. Glucocorticoids, small molecular substances, and antibody-based therapies are the classes of agents used to treat acute rejection as first-line therapy. A number of combination therapy regimens, with different protocols, can be used6  principally to avoid side effects induced by high dosages of single therapies.
In a phase III study, an interleukin-2 receptor antagonist (anti-CD25 antibody, basiliximab) was used to prevent acute rejection episodes in renal allograft recipients.

Late dysfunction
Late dysfunction occurs a few months after transplantation and the most common late dysfunction is chronic rejection. Pathologic changes of chronic rejection have been documented for many years. The transition from acute to chronic rejection is not clearly demarcated, as many biopsies show evidence of both, and some characteristic changes of chronic rejection have been reported as early as ten days post-transplantation. The etiology of chronic rejection is still controversial, with possible sources being immune mechanisms, ischaemia and hyperfiltration.

Regardless of whether chronic rejection is exclusively immune-mediated, acute rejection remains the strongest predictor of chronic rejection. It is widely believed that the primary lesion is an obliterative endarteritis sometimes associated with obliterative capillaritis of the glomeruli. The new classification is reflective of differences in mechanism, treatment and prognosis in these different forms of rejection: rejection is graded as borderline; active/acute, as in Type 1 if it is primarily interstitial; Type 2 if there is intimal arteritis; Type 3 if there is transmural arteritis.

Treatment
As kidney transplantation has excellent short-term outcomes but long-term graft survival has not improved in a parallel fashion, the present goal of immunosuppressive therapy is to balance the beneficial effects of reducing acute rejection while minimising adverse effects of over-suppression, including the development of infections, malignancy and cardiovascular risk factors. In general, current immunosuppressive protocols use combinations of immunosuppressive agents, with different mechanisms of action to maximise efficacy and minimise the toxicity of each drug. Over the past decade there has been a growing interest in identifying regimens that allow the minimisation of calcineurin inhibitors (CNIs) in an attempt to decrease nephrotoxicity and metabolic side effects. The emergence of new immunosuppressive agents and tolerance protocols appears promising as a means of delivering immunosuppression without long-term toxicity. Concerns about the side effects of chronic steroid therapy, such as weight gain, hyperlipidemia, diabetes, hypertension and bone disease have prompted increasing interest in steroid-free immunosuppression.

Given the low acute rejection rates, the paradigm for immunosuppression today has shifted from maximising immunosuppression to exploring alternatives and safe protocols for minimising drug therapy. Ultimately, the goal of prescribing immunosuppression is to move from empiric therapy to individualised therapy.

Immunosuppressive drugs
Current immunosuppressive drugs can alter the response of lymphocytes or antibodies to heterologous proteins. Usually, different immunosuppressive agents are combined so that each can focus against a different molecular target within the rejection response. Synergistic effects are therefore achieved by using low-dose drug combinations, which reduce the specific toxicity while enhancing the immunosuppressive action of each. Current immunosuppression protocols recommend the use of CNIs (for example, ciclosporin and tacrolimus) in more than 95% of transplants, despite the interest in identifying regimens that allow minimal CNI use over the last decade.
Based on the mechanism of action, immunosuppressors are classified as follows:
1. Selective inhibitors of cytokine production and function
Cytokines are soluble signal proteins and non-specific to the antigens that induced their production, and bind the surface receptors of many different cells. Cytokines include interleukins (IL), interferons (IFN), tumour necrosis factors (TNF α and β), transforming growth factors and colony-stimulating factors. IL-2 stimulates the production of helper T-cells as triggered by the antigen and after activation, it produces more IL-2, IFN-γ and TNF-β. These cytokines together activate natural killer cells, macrophages and cytotoxic T-cells. Drugs interfering with IL-2 production or activity reduce the immune response, thus preventing graft rejection.

Ciclosporin and tacrolimus are probably the most effective immunosuppressive drugs in clinical practice, and these drugs target the intracellular signaling stimulated after activation of T-cell receptors. Even though they are not correlated from a structural perspective and they bind to discrete, yet similar molecular targets, both inhibit signal transduction with the same mechanism and are used in allogenic kidney, liver, heart, lung and other organ transplants to prevent rejection.

The principal side effect of these drugs is the dose-dependent nephrotoxicity caused by the vasoconstriction of the renal arteries, which produces irreversible structural damage in the long term, with interstitial fibrosis and glomerular damage progressing to chronic renal failure. Other adverse effects are hypertension, hepatotoxicity, hyperlipidemia (increase in LDL cholesterol), hyperkalemia, hyperuricemia, hypomagnesemia, peripheral neurotoxicity, increased bilirubin levels, cholelithiasis, hirsutism, diabetes mellitus and gum hyperplasia.

Sirolimus and everolimus are mammalian targets of rapamycin (mTOR) inhibitors, and are macrolides that can block the transduction of the IL-2 signal and inhibit progression along the cell cycle.10

2. DNA synthesis inhibitors or immunosuppressive antimetabolites, such as azathioprine and mycophenolate (mofetil and sodium), are often used in association with glucocorticoids and CNIs.

3. Monoclonal and polyclonal antibodies that block T-cell surface molecules are anti-CD3 monoclonal antibodies, and include muromonab-CD3 (OKT3); anti-IL-2 receptor monoclonal antibodies (anti CD-25); basiliximab, daclizumab and alemtuzumab; and lymphocyte proliferation inhibitors: antithymocyte globulins (ATG or RATG).

Mono- and polyclonal antibodies against lymphocyte surface antigens are widely used in the prevention and treatment of acute rejection in organ transplantation. These antibodies are prepared with animal vaccines (horse, rabbit, sheep or goat) and (polyclonal) human lymphoid cells, or by using the hybridoma technique, which produces monoclonal antibodies. The antibodies bind to the surface of the circulating T-lymphocytes, and the cells bound to the antibodies are then opsonized and absorbed by the liver and spleen, with subsequent lymphopenia and alteration of the T-cell response.

4. Adrenocorticosteroids, such as methylprednisolone sodium hemisuccinate and prednisone, are steroids that cause non-specific immunosuppression and can rapidly reduce the lymphocytic population through lysis, or redistribution mechanisms. Steroids bind to intracellular receptors, and these receptors and the proteins induced by the glucocorticoids bind to the DNA near regulation elements that modulate the transcription of many genes, leading to an improvement in long-term outcomes. Also, the glucocorticoid-receptor complex increases the IkB (Ikbeta proteins) expression, therefore blocking the NF-KappaB (NF-KB, the eukaryotic transcription factor) activation, which increases the apoptosis of the activated cells. Once again, the crucial aspect is the suppression of important proinflammatory cytokines, such as IL-1 and IL-6, the inhibition of IL-2 production in the T-cells, and relevant proliferation. The activation of cytotoxic T-lymphocytes is inhibited as well, and there is less chemotaxis, and a lower release of neutrophil and monocyte lysosomal enzymes. Therefore, from an anti-inflammatory perspective, glucocorticoids have a strong effect on cell immunity, but little effect on humoral immunity. The extensive use of glucocorticoids causes disabling and potentially lethal adverse reactions in many patients. These side effects include growth retardation, vascular osteonecrosis, osteopenia, higher risk of infection, poor wound healing, cataracts, hypercholesterolemia, hypertrigliceridemia, acne, behavioral changes, weight increase, arterial hypertension, glucose metabolism alterations with onset of metabolic syndrome, and diabetes mellitus.

Anti-CD3 monoclonal antibodies
Antibodies against the ε-chain of the CD3 antigen on the surface of human T-lymphocytes have been used since the early 1980s, proving to be extremely effective immunosuppressors. Their principal side effect is the “cytokine release syndrome”. The antibody’s bond to the T-cell receptor and to the Fc receptor (FcR) is the foundation of the initial activation caused by this drug. The syndrome is associated with, and attributed to, an increase in serum cytokines (including tumour growth factors such as TNF-α, IL-2, IL-6 and interferon-γ), which are released by the activated T-cells and/or by the monocytes. TNF-α production is known to be the greatest cause of toxicity and clinical manifestations are typically high fever, shivers, stiffness, migraines, tremors, nausea, vomiting, diarrhoea, abdominal pain, indisposition, arthralgia and myalgia, and asthenia.

Anti-IL-2 receptor monoclonal antibodies (anti CD-25)
Monoclonal antibodies against the IL-2 receptor (basiliximab and daclizumab) have become increasingly important in immunosuppression in the past ten years, especially in immunosuppression induction, because of their ability to reduce the incidence of acute rejection with a near absence of side effects. This subsequently reduces the incidence of chronic rejection and improves graft function.

Though neither antibody is associated with cytokine release syndrome, they can cause anaphylactic reactions. They can also cause lymphoproliferative disorders and opportunistic infections, like all other immunosuppressive drugs, though the incidence of such complications appears to be remarkably low.

Lymphocyte proliferation inhibitors: antithymocyte globulins (ATG or RATG)
Thymocytes are cells that develop in the thymus and serve as T-cell precursors. Polyclonal antibodies were developed to act against thymocytes and are xenogenetic molecules that can cause severe side effects, including fever and shivers, and are also possibly associated with arterial hypotension.
Pre-treatment with corticosteroids, paracetamol and/or an antihistaminic, administered slowly (6–10 hours) via central venous access, minimises such reactions. Side effects also include serum-induced indisposition and glomerulonephritis, and anaphylaxis is considered rare.
Haematologic complications
of the treatment include leukopenia
and thrombocytopenia. As with other immunosuppressors, there is a greater risk of infection (especially cytomegalovirus (CMV) -related)
and tumours.10

Conclusion
There is currently no commonly accepted ideal immunosuppressive regimen, though individually tailored immunosuppressive regimens are considered current best practice.

These individually tailored regimens allow for a specific immunosuppressive protocol to be used according to patients’ needs, by choosing the most suitable, well-tolerated combination of agents, and effective doses.

This results in reduced episodes of acute rejection (both in incidence and severity), reduced drug-related toxicity and side effects, and an increase in short-term and, long-term graft and patient survival.

The individually tailored immunosuppressive regimens currently avoid CNI regimens, or use these sparingly as a response to CNI-induced toxicity. Most of these CNI-avoidance regimens instead favour mTOR inhibitors, aiming for long-term improvement in kidney function, reduced risk of chronic renal failure, limited cardiovascular damage and possible reduction in CNI-related post-transplantation cancer.

Furthermore, regimens avoiding or reducing the use of steroids aim to eliminate or reduce steroid-induced toxicity, and are feasible in kidney transplantation, showing a reduced incidence in post-transplant diabetes, CMV infections, arterial hypertension, bacterial infections and hypercholesterolemia

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