Acute rejection can be prevented by appropriate immunosuppressive therapy. Higher doses of immunosuppressant are used for the 1st three months after transplantation where the risk of acute rejection is the highest. Once the severe damaged parts of graft are healed by fibrosis and the remainder of graft can function normally, the immunosuppressant doses can be reduced. Current standard immunosuppressant is efficient and well-tolerated by patients. The frequently prescribed immunosuppressant drugs are Calcineurin inhibitors (CNIs), Mycophenolate mofetil (MMF) and Steroids which may or may not use together with induction therapy. Each immunosuppressant has different specific dose-dependent negative effects but all of them will increase the risk of having malignancy and infection1, 7.
Cyclosporine and tacrolimus are CNI. They are used in most of kidney transplant recipients. Before drug-receptor complex binds to and inhibits calcineurin, cyclosporine and tacrolimus bind to specific immunophilins (e.g. cyclophilin and FK binding protein, respectively). Cyclosporine and tacrolimus play a role in dephosphorylating of a variety of transcription factors, especially nuclear factor of activated T cells (NF-AT). NF-AT sites exist in the promoter regions of IL-2, IL-3, IL-4, granulocyte-macrophage colony stimulating factor, interferon gamma (INF-gamma), and TNF-alpha. NF-AT is critical in transcribes these cytokine genes in response to activating signals via T cell receptor. This means that CNI primarily interferes with the signal 2 of T-cell activation. Hypertension, nephrotoxicity, neurotoxicity, and dyslipidemia are the common side effects of cyclosporine and tacrolimus13.
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After administrated CNI, there is an initial absorption phase with the concentration in blood reach peak level (Cmax) after 2 to 3 hours. Drug concentration decreases during elimination phase. This fall is due to metabolism. Cyclosporine is extensively metabolized by the cytochrome P450 3A4 system1, 3. Any drugs that interact with the P450 3A4 system will influence the level of cyclosporine. For examples, verapamil, azithromycin, fluconazole, amiodarone and others are some of the medications that inhibit the P450 system and increase CNI levels. On the other hand, rifampin, carbamazepine, terbinafine and others are some of the medicines that interact with CNI and reduce CNI levels13. Next dose is immediately given to patient when CNI concentration reached the trough level (C0). The interpatient and intrapatient variability for both CNI is mainly due to absorption phase instead of elimination phase. Blood-level Monitoring is required for both cyclosporine and tacrolimus as they have narrow therapeutic index1, 3.
Cyclosporine was first invented in a corn oil-based (which is Sandimmune). It had wide varied bioavailability among patient that range from 1 to 89%. Time taken for solubilize cyclosporine in bile is not only one of the reasons that affects absorption and result in varied bioavailability. There are other factors that cause this variation. These include time of day, present or absence of food, race, kidney function, time for gastrointestinal transit, and gastrointestinal autonomic neuropathy. Also, during early post transplantation period absorption is enhanced. Thus, reduced dosage is needed. In the case of metabolism, it is only affected by liver disease and variation in the activity of CYP450 3A4. This has led to development of microemulsion cyclosporine (Neoral) to reduce this variability. Neoral has a better and more consistent absorption than Sandimmune even absorption still significantly vary1, 3, 13.
Tacrolimus is similar to cyclosporine in intrapatient and interpatient variability for the absorption1. Tacrolimus has a half-life from 31.9 to 48.1 hours. It has a volume of distribution of 0.85-1.94 L/kg13. It has a rapid absorption with the peak levels achieved within the first 3 hours after administration. Its absorption is affected by transition time in gastrointestinal and presence or absence of food. Daily dosage requirements are also depend on patient age, gender, race, and body mass index (BMI). Fat content in food, duration of having tacrolimus, serum albumin, haematocrit, and presence of disease in liver like hepatitis B or C infection are the affecting factors too. Modified-release tacrolimus once-daily has therefore developed to have an equivalent pharmacokinetic profile1.
Meta-analysis of tacrolimus and cyclosporine had shown similar outcomes in graft survival. However, some analyses have shown that tacrolimus provided better rejection prophylaxis with slightly better graft survival. This is confirmed by several recent trials but these trials had failed to show any benefit in graft survival1. Thus, tacrolimus is suggested by NICE to use as a primary immunosuppression in kidney allograft recipients or in patients with kidney allograft rejection that does not response to conventional immunosuppressive regimens. It can be given by intravenously or orally. Oral tacrolimus therapy is given initially at the dose of 150-300 μg/kg per day. The dose is then adjusted according to whole blood or plasma trough concentrations. Tacrolimus is also licensed to treat acute kidney rejection. A patient weighing 70 kg is suggest with an initial doses of 150-300 μg/kg daily will cost about £16.30-£32.60 per dose10.
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Mycophenolate mofetil (MMF) is other immunosuppressant which is recommended for adults as part of an immunosuppressive regimen when patients are intolerance to CNI or when there is a high risk of nephrotoxicity where the usage of CNI should be avoided. In most units worldwide, MMF is now used as a primary therapy in place of azathioprine. The recommended oral dose for MMF is 1 g twice daily in the presence or absence of food. It can be increased to a maximum daily dose of 3 g. Dose adjustment is not required even there is a heart, kidney or liver failure presence. MMF monotherapy is not recommanded1, 2, 5, 6, 13. It is indicated to be used together with ciclosporin or tacrolimus and corticosteroids for the prophylaxis of acute transplant rejection14. This is because synergistic effect in these combination regimens allows dose reductions in immunosuppressive drugs while maintaining its immunosuppressants efficacy. Lower doses used will therefore reduce the drug-specific side-effects. For example, MMF is able to facilitate sparing of cyclosporine and thus reduced cyclosporine-related-nephrotoxicity1, 5, 6, 13. Mycophenolate mofetil is licensed used in initial and maintenance therapy. A dose of 2 g of mycophenolate mofetil costs about £910.
Mycophenolate mofetil (MMF) exhibit its effect by inhibiting the production of guanosine nucleotides to prevent DNA synthesis occurs. Thus, the proliferation of T and B cells is inhibited too. Also, the glycosylation of adhesion molecules, which are involved in attaching lymphocytes to endothelium and the potentiating leukocyte infiltration during an immune response, are inhibited by MMF6, 13.
Mycophenolate mofetil is the prodrug of Mycophenolic acid (MPA). The mycophenolate mofetil (MMF) has good bioavailability of 94% and the absorption is almost complete. Once absorbed, all MMF is rapidly converted to MPA. MPA is then converted into mycophenolic acid glucuronide [MPAG] by glucuronidation in liver. MPA peak occurs after 1 hour oral administration. This is then rapidly declines with the second peak form at 6-12 hours. This leads to terminal half-life of around 16 hours. The second peak is the result of MPAG deconjugated to MPA by colonic bacteria and absorb back through enterohepatic circulation. MMF (MPAG [87%] and MPA [6%]) is excreted majorly through urine with only 6% is excreted through faces. Total MMF absorption is not affected by food. However, in the presence of food, MPA Cmax is reduced by 40% and delayed for almost two hours. 97% of MPA and 82% of MPAG will bind to albumin. Since MPA binds to plasma albumin is concentration-dependent, increase MPA concentration will decrease albumin-bound-MPA5, 13.
Even though, there is a higher direct cost for using MMF when compared to azathioprine (AZA), MMF effectively treated and decreased the incidence of acute rejection in patients. Thus, it is use as a cost-effective option for the first year after transplantation. This is support by the data pooled from Sollinger and the US Renal Transplant Mycophenolate Mofetil Study Group, The European Mycophenolate Mofetil Cooperative Study, The Tricontinental Mycophenolate Mofetil Renal Transplantation Study Group were analysed after 1 year. It showed that 2 or 3 g/day MMF significantly did better than placebo or AZA in reducing the incidence of graft loss due to acute rejection. The requirements for the treatment of anti-lymphocyte globulin and the full courses of steroids to treat rejection were reduced in the MMF treatment groups. However, the numbers of severe opportunistic infections were higher in the MMF 3 g/day than in MMF 2 g/day, placebo or AZA groups1, 2, 5, 6.
The adverse reactions associated with MMF are limited to gastrointestinal and hematologic. These include gastrointestinal side effects (e.g. abdominal pain, vomiting, and diarrhoea), anaemia, leukopenia, infections and malignancy. Adverse effects can be reversed quickly once the drug discontinue. This is because MMF inhibits purine synthesis at the late stage of proliferation. MMF can interact with several drugs like acyclovir, probenecid, cyclosporine, tacrolimus, and magnesium or aluminium hydroxide antacids. For example, cyclosporine decreases its concentration whereas tacrolimus increases its concentration. In certain conditions like liver disease and low albumin, drug level can be altered. Since each patient have different area under curve (AUC) for MMF, monitoring the drug level is therefore required5, 13.
Corticosteroids have been used as a mainstay for about 50 years in both the prevention and treatment of renal allograft rejection4. Corticosteroids suppress antibody and complement binding. Corticosteroids act primarily on activated T cell. So that, the production of T cell cytokines such as IL-2, IL-6 and interferon-gamma can be inhibited. The roles of these T cell cytokines in enhancing the response of lymphocytes and macrophages to allograft antigens can be prevented too. It also stimulate T cells migrate from the intravascular compartment to lymphoid tissue13. Here, prednisone is the most widely used. It is metabolized primarily in liver to its major active metabolite known as prednisolone. Prednisone has a time-concentration curve which is same as cyclosporine and tacrolimus. It shows a peak after 2-3 h administration with no measurable levels by 24 h12. Mostly, there is a clinical insignificance interaction between corticosteroids and other drugs. For example, cyclosporine can increase prednisolone in plasma concentration12, 13.
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The usage of corticosteroid will however increase the risk of infection, gain weight and psychiatric disturbances (e.g. mood swings and depression). It also has adverse effects on bone (e.g. osteopenia, aseptic necrosis), dermatological (e.g. acne, and easy bruisability/ ecchymoses), and cardiovascular (fluid retention, hypertension, hyperlipidemia, and glucose intolerance). Early post-transplant osteopenia is suggested to be the effect of corticosteroids too. According to Astellas study, a follow-up after five years had confirmed that the early corticosteroid withdrawal will have the lower long term incidence in fractures or avascular necrosis than corticosteroid maintained group. This effect is still unclear as it may be complicated by many other factors (e.g. renalosteodystrophy). These unwanted adverse effects have therefore motivated people to develop corticosteroid-free regimens. Therefore, a paradigm shift to early withdrawal or completely eliminate corticosteroid has shown in the past decade. In corticosteroid-free regimens, CNI and MMF are used and induction antibodies therapy is normally involved4.
Withdrawing of corticosteroid is still remains concern. This is because according to European-based ATLAS study, there is a higher chance of acute rejection in patients without corticosteroids than those with corticosteroids immunosuppressant. In the Astellas Steroid Withdrawal Study, it also showed that the incidences of acute rejection in the early corticosteroid withdrawal group (used for first 7 days after transplantation) were higher than corticosteroids maintenance group after 5 years follow-up. Also, recently, there are some published trials started to concern about the long-term graft fibrosis. Since the rate of fibrosis had been increased in corticosteroid-free group, the effect of corticosteroids which provide protect against fibrosis development was started to be question. Renal dysfunction is then evaluated by some biopsies. It shows that chronic allograft nephropathy (CAN) was higher in patients who have withdrawn from corticosteroids than the patients who have maintained on prednisone for 4 years. Therefore, the wisdom of withdrawing corticosteroids still under controversial, especially for those patients who are at high risk of immune like highly sensitized or African-Americans patients4.
Induction therapy is a course of immunosuppression that takes about 2 weeks immediately before or after transplantation. Induction therapy reduced the incidence of accelerated rejection and acute rejection after transplantation by 'turned off' the immune system. Also, it used to reduce the usage of calcineurin inhibitors in the early stages of post-transplantation when nephrotoxic effect cannot be tolerated10. Polyclonal antibodies antithymocyte immunoglobulin (ATG), antilymphocyte immunoglobulin (ALG), monoclonal antibody muromonab-CD3 (OKT3) and Anti-interleukin-2 receptor (IL-2R) antibody are some of the examples that can be used in induction therapy. However, only a few induction therapies that are widely use as rejection prophylaxis following organ transplantation will be discussed over here.
In low immunologic risk patients, anti-IL-2 receptor (IL-2R) antibodies are more preferable than polyclonal antibodies which are more toxic8. Basiliximab or daclizumab is recommended by NICE guideline to use as part of a calcineurin-inhibitor-based immunosuppressive regimen for the prophylaxis of acute organ rejection in recipients who undergo renal transplantation10.
Both basiliximab (Simulect, Novartis) and daclizumab (Zenapax, Hoffman-La Roche) are humanized anti-interleukin-2 (IL-2) receptor IgG1 monoclonal antibodies are approved to use as rejection prophylaxis following organ transplantation. They are given in a short course after transplantation. Randomised controlled trials had shown that both of them had reduced the prevalence of acute cellular rejection by about 40%. Basiliximab and daclizumab are appearing to be equally safe and efficacious. Basiliximab and daclizumab are biologically engineered to have more human genes and less murine-derived genes. So, they have fewer side effects. It is reported that anaphylaxis is only adverse effect but the risk of lymphoproliferative disorders is suspected too7.
These monoclonal antibodies will target the α-subunit (CD25) of the interleukin-2 receptor (IL-2R) on activated T cells. This will block the IL-2 induced lymphocyte proliferation and thus acute graft rejection is prevented9.
Basiliximab has a volume of distribution in an adult's litres with the half-life of 7.2 days. Its clearance is about 41 mL/min13. It is licensed to use in concomitantly with ciclosporin microemulsion and corticosteroid-based immunosuppression as a prophylaxis in patients with panel-reactive antibodies less than 80% to avoid acute kidney rejection after kidney transplantation. Also, it can be used in a triple-maintenance immunosuppressive regimen that includes microemulsion ciclosporin, corticosteroids and either azathioprine or mycophenolate mofetil. It is given in a total two doses of 20 mg each. One dose of basiliximab costs about £84010.
Daclizumab is the first humanized mAb for renal organ transplantation. Daclizumab has a volume of distribution from 0.032 to 0.043 liters/kg. It is estimated to have a half-life of 20 days13. According to NICE guideline, it is licensed to use in concomitantly with other immunosuppressant like ciclosporin and corticosteroids for the prophylaxis of acute kidney rejection in patients who are not highly immunised10. However, there was a trial which shows that patients who had received daclizumab (Zenapax) had a higher mortality when compared those received placebo. So, daclizumab is discontinued14.
Rabbit anti-human thymoglobulin (ATG) is a polyclonal antibody. ATG acts on all types of T lymphocytes and depletes them. ATG offers a better antirejection activity than both no induction therapy and induction with non-depleting antibodies in high immunologic risk patients. Second graft recipients, hypersensitized patients and black patients are belongs to this group. Polyclonal antibody therapy may be more potent than anti-IL-2 receptor antibodies8. After 5 years follow-up, corticosteroid-free group in the Astellas trial showed that the incidence of acute rejection in patients who received anti-IL-2 receptor antibody is more than those who received rabbit-antithymocyte globulin4. However, the risk of having neoplasm may also increase when induction therapy is used together with other potent immunosuppressant. So, the rates of infection or neoplasm for basiliximab and ATG were then compared. In the comparison, it showed that basiliximab have a lower risk in both infection and neoplasm than ATG. Therefore, anti-IL-2 receptor antibodies are more preferable to be used11.
Sirolimus (Rapamycin) is a mammalian target of rapamycin (mTOR) inhibitor. Sirolimus is licensed to use as a prophylaxis to prevent organ rejection in adult recipients who are at low to moderate immunological risk. Sirolimus is recommended as part of an immunosuppressive regimen when patients are intolerance to CNI due to nephrotoxicity and require complete withdrawal of these treatments10.
Sirolimus inhibit p70S6 kinase, which is responsible in phosphorylates 40S ribosomal protein S6, by binding to FK Binding Protein (particularly FKBP-12) and modulate the activity of mammalian target of rapamycin (m-TOR). Thus, this enable sirolimus express its immunosuppressive activity primarily by blocking IL-2 and IL-15 induction of B and T cell proliferation. This prevents progression of the cell cycle from the G1 to S phase. This means that sirolimus allows T cell activation but prevents these cells from proliferating in response to IL-213.
Sirolimus is very lipophilic. So, it is incorporate into oily solution or micro-emulsion to improve its absorption. However, its absorption is reduced in African Americans and in diet with high- fat content. Sirolimus has a half-life of approximately 60 h. It is licensed to give once daily in kidney recipients as a prophylaxis. Sirolimus is bound extensively to plasma proteins. Sirolimus is metabolized by the P450 3A4 in liver. So, any drugs that inhibit or induce this system can affect the concentration of sirolimus. For example, erythromycin, fluconazole, and protease inhibitors, which inhibit sirolimus metabolism, lead to sirolimus potentially toxic levels. Phenytoin, which activate sirolimus metabolism, leads to sirolimus sub therapeutic levels. Its elimination normally occurs at 57 to 63 hours after administration. Steady state is normally reached 5 to 7 days after dose adjustment. The sirolimus eliminates mainly in faeces13.
The side effects associated with sirolimus are arthalgias, aphthous ulcers, hyperlipidemia, interstitial pneumonia (is an uncommon complication but potentially life-threatening) and cytopenias such as thrombocytopenia, anemia and leucopenia. When sirolimus is used together with cyclosporins (not tacrolimus), there is a higher chances of getting nephrotoxicity13.
Recent studies had suggested that CNIs cannot be substituted by m-TOR inhibitors at the beginning of post-transplantation. This is because m-TOR inhibitors have lower efficacy and unfavourable side-effect profile, especially in wound healing problems. However, m-TOR inhibitors can be safely substituted CNI at 3 months after transplantation with improvement in kidney function were suggested by some other researches1. Therefore, the combination of sirolimus, microemulsion ciclosporin and corticosteroids is recommended to be used for the first 2-3 months after transplantation by NICE. According to the marketing authorisation, sirolimus can be continued as maintenance therapy with corticosteroids alone if ciclosporin can be stopped eventually. Thus, the sirolimus is usual given as a 6 mg oral loading dose soon after transplantation, then followed by 2 mg once daily. The sirolimus dose should be individualised. A whole blood trough levels with 4-12 ng/ml should be obtained. In a tapering regimen of corticosteroids and ciclosporin microemulsion, Sirolimus should be optimised with a suggested ciclosporin trough concentration ranges of 150-400 ng/ml for the first 2-3 months after kidney transplantation. After ciclosporin progressively discontinue over 4-8 weeks, the sirolimus is adjusted to obtain trough levels of 12-20 ng/ml in whole blood10. Sirolimus is usually given together with corticosteroids for cyclosporine withdrawal from combination therapy with cyclosporine with sirolimus administer after 4 hours of cyclosporine1. In an unsuccessful ciclosporin withdrawal patient, the combination of ciclosporin and sirolimus should not be used exceed 3 months after kidney transplantation. Once sirolimus discontinued, an alternative immunosuppressive regimen can be substituted. A dose of 4 mg sirolimus costs £12 per day. 6 mg of sirolimus is used immediately after transplantation, followed by 2mg daily for the first 2-3 months with the combination of ciclosporin. After that an average of 4 mg of sirolimus is given per day10. However, the narrow therapeutic of sirolimus which required regular therapeutic drug monitoring, had led to development of everolimus (a sirolimus derivative) with improved physicochemical properties13.
In conclusion, Basiliximab, daclizumab, tacrolimus, MMF and sirolimus are newer immunosuppressant drugs than ciclosporin, AZA and corticosteroids. These new and older drugs are the options which are suggested by NICE guideline to use as a prophylaxis in rejection except for daclizumab which has been discontinued10. Mostly, these newer drugs are more effective or less side effects than the older drugs. So, they can substitute or use as an alternative to others old drugs. Current guidelines only suggest the choice of regime for treatment rather than prophylaxis. Thus, the drugs selection for this 42 year old patient should depend on his/her personal factors like his/her kidney or liver function and the ability for his/her to tolerance the drugs. Also, the past medicine history and drug history of this patient should be consider to prevent any interaction occur which leads to sub-therapeutic (e.g. result in rejection precipitate out) or over-therapeutic (e.g. leads to drug toxicity).