Kidney transplantation is a surgical process transferring a kidney from one persons body to another persons body. It may involve the transfer of a kidney from a healthy person or the deceased to the recipients who are suffering from end stage chronic kidney disease or more commonly known as kidney dysfunction. There are many causes which lead to kidney dysfunction, and thus the necessity of kidney transplantation. Among them are diabetes (which is the commonest cause of kidney failure), nephrosclerosis (caused by chronic hypertension), chronic glomerulonephritis, polycystic kidney disease, systemic lupus erythematosus and interstitial nephritis. Despite the fact that human is able to survive with only one kidney, kidney donation is generally not accepted and practiced by most people as the statistical value in UK from April 2010 to April 2011 showed that most of the kidney donations were from the deceased, which were 1667 donations instead of living donations, which were only 1020 donations. It was found out that there is a higher prevalence of chronic kidney disease among communities of South Asian and African or Carribbean ethnic origin, and yet the donors from the communities are very few.
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Kidney transplantation is vital in reducing the burden of patients. Patients who had undergone kidney transplantation do not need to perform dialysis, which is very time-consuming, thus improving life quality of the patients. It would also prolong the life expectancy of patients with end stage renal disease. However, there are great concerns with the postoperative complications such as delayed function of the transplanted kidney, rejection of foreign kidney by the patients’ own bodies, deep vein thrombosis and some other complications caused by the immunosuppressant drugs administered, for example hypertension, diabetes mellitus, infections and thrush. Among them, graft rejection by patients’ own immune system is the most hazardous, as the function of the transplanted graft would cease and it sometimes would require the patients to undergo surgery to remove the graft from their bodies and perform another kidney transplantation surgery. Sometimes graft rejection might lead to the death of the patients, about 10% of the patients died annually. However the risk of graft rejection could be greatly minimised by the administration of immunosuppressants to the patients.
After kidney transplant surgery, the patients have to administer a range of medications. The medications administered at early phase after the kidney transplantation are aimed to prevent the incident of acute rejection of foreign kidney by patients’ bodies, to optimize the function of the transplanted kidney as well as to prevent infections at site of surgery. Meanwhile, the medications administered at the later phase after the kidney transplantation are aimed at maintaining the well function of the transplanted kidney and preventing the side-effects of administering the immunosuppressant drugs for a long period of time, i.e. malignancy, infections, osteoporosis and cardiovascular disease. There are many types of immunosuppressant drugs being used in practice nowadays, namely calcineurin inhibitors, antiproliferative agents, mTOR inhibitors and steroids. Calcineurin inhibitors are the most commonly used immunosuppressants, either during the induction of immunosuppression or the maintenance therapy, whereas the other types of immunosuppressants are often used as an adjuvant to the calcineurin inhibitors.
Calcineurin inhibitors (CNI) are potent immunosuppressants which act by blocking the phosphatase protein, calcineurin. Calcineurin is a serine phosphatase which once activated by calmodulin, would bind to and dephosphorylate inactive nuclear factor of activated T cells (NFAT). The translocation of the activated NFAT into the nucleus and association with other transcription factors, such as AP-1 leads to a range of events which would subsequently result in the activation of T-cells and the production of cytokines such as Interleukin-2, which could attack the ‘non-self’ cells (in this case transplanted kidney). Examples of calcineurin inhibitors being used in practice nowadays are Cyclosporine and Tacrolimus. Both the CNI bind to immunophilins in T-lymphocytes (where Cyclosporine binds to Cyclophilin A, while Tacrolimus binds to FKBP 12), form drug-immunophilin complexes which have a higher affinity of binding to calmodulin-activated calcineurin. This would subsequently inhibit the binding and association of the calmodulin-activated calcineurin to NFAT, thus preventing the occurrence of the range of events in the activation of T-cells and reducing the risk of rejection of the graft by patients’ immune system. Both the CNI Cyclosporine and Tacrolimus were shown to be capable of preventing the asscociation of calcineurin with other proteins, such as IKB, Na-K-ATPase and nitric oxide synthase, resulting in side-effects of calcineurin inhibition.
Cyclosporine (C62H111N11O12) is a large, cyclic, highly hydrophobic endecapeptide molecule with a molecular weight of 1203. It has the amino acid N-methyl-(4R)-4-butenyl-4-methylthreonine in position 1, sarcosine in position 3 and D-alanine in position 8.7 Most of its amino acids are N-methylated and this served as protection from the degradation of cyclosporine in gastrointestinal tract. Cyclosporine is partially soluble in water and saturated hydrocarbon solvents, while it is very soluble in lipids and other organic solvents. According to British National Formulary (BNF), the dose of cyclosporine when being administered as monotherapy to patient before the transplantation surgery is recommended to be taken orally 10-15 mg/kg every 4 to 12 hours for three months. However the recommended dose is adjusted to 10-15 mg/kg daily for 1 to 2 weeks after the transplantation surgery and further reduced gradually to 2-6 mg/kg daily for maintenance therapy. In addition, the dose of the cyclosporine should be lowered if it was being administered simultaneously with other immunosuppressive agents. However as varies bioavailability of cyclosporine among different patients due to factors of age, ethnicity, gastrointestinal secretions of bile and comorbidities, the dose of cyclosporine should be tailored or adjusted individualised for each patient. The volume of distribution of cyclosporine is about 4-8 L/kg and it is highly lipid soluble, it is found in a higher blood concentration in leukocyte-rich and high-lipid content organ. Cyclosporine is carried, mainly by the lipoproteins in the plasma and transported throughout the body. Cyclosporine is metabolised mainly in the liver by the enzyme CYP3A4, which is one of the members of the cytochrome P450 superfamily and excreted mainly in bile (about 90%). Most of metabolites of cyclosporine exhibit only a little immunosuppressive effects. Cyclosporine is contraindicated in pregnancy and breast-feeding women as it would cross the placenta and also be excreted in human milk. Example of the brands that cyclosporine is available in the market are Capimune®, Deximune®, Neoral® and Sandimmun®. As different brands of cyclosporin preparation release different amount and being released at a different rate from the preparation, so patients are advised not to simply change their cyclosporine brand.
Tacrolimus (C44H69NO12•H2O) is a macrolide lactone antibiotic with a molecular weight of 804. It is insoluble in water, but is partially soluble in saturated hydrocarbon solvents. On the other hand, it is very soluble in lipids and other organic solvents. The commonest brand of Tacrolimus being used in practice is Advagraf®, a sustained-release capsule. According to BNF, the dose of Advagraf® when being administered to patient before the transplantation surgery is recommended to be taken orally 200-300 micrograms/kg once daily in the morning and it should be administered to the patient within 24 hours after the transplantation surgery.9 Tacrolimus is also available in other different formulations and brands, for instances the immediate-release capsules with brands Adoport®, Prograf® and Vivadex® , which are being administered orally to the patients twice daily (once in the morning and once in the evening); and Modigraf® granules which are used to prepare an immediate-release oral suspension, which is being administered to patients twice daily (once in the morning and once in the evening). Although the bioavailability of tacrolimus is not influenced by factors of age, ethnicity, gastrointestinal secretions of bile and comorbidities, the absorption of tacrolimus is greatly varied among patients and is affected by the fat-content of the food ingested (the higher fat content of the food ingested, the slower would be the rate of absorption and the lower bioavailability). Moreover the clearance of tacrolimus was found to be faster in pediatric patients compared to elder patients, which required a higher dose for the pediatric patients. Therefore the dose of tacrolimus given to every patient should also be tailored or adjusted individualised for each patient. Following absorption of the tacrolimus in intestine, tacrolimus distributed mainly into the red blood cells of patients rather than plasma, leads to its higher whole-blood concentration when compared to its plasma concentration. In contrast to cyclosporine, tacrolimus does not bind to lipoprotein in plasma; it binds to an acute phase protein i.e. α1-acid glycoprotein instead.7 Tacrolimus is metabolised in a similar route as cyclosporine, mainly in the liver by enzyme CYP3A4. Among the metabolites of tacrolimus, the main metabolite 31-0-demethyl-tacrolimus was shown to exhibit a significant immunosuppressive action. Tacrolimus is contraindicated in pregnancy and breast-feeding women due to its ability to move across the placenta and also be excreted in human milk.
Both the CNI cyclosporine and tacrolimus have been found to be not only capable of blocking the calcineurin-dependent/NFAT pathways but also the other two pathways which are also responsible in activation of AP-1 (which would then leads to the initiation of a series of immune response), namely the Jun N terminal kinase and p38 signaling pathways. The high specificity of calcineurin inhibitors in exhibiting their immunosuppressive action than other classes of immunosuppressant is attributed to their ability in inhibiting both the Jun N terminal kinase and p38 signaling pathways. Nevertheless the bioavailability and the clearance of cyclosporine and tacrolimus are greatly affected by the CYP3A4 system and the P-glycoprotein. Any substance which is competitively inhibiting the action of CYP3A4 system is also found to have an inhibitory effect on the P-glycoprotein, which might eventually lead to CNI toxicity due to the increased bioavailability. In contrast, substances which could induce or stimulate activity of the CYP3A4 system and the production of P-glycoprotein would decrease the bioavailability of CNI administered to transplantation surgery patients, thus putting the patients on a higher risk of graft rejection due to the suboptimal therapeutic dose of immunosuppressants. The most manifest side-effect of the CNI immunosuppressants is nephrotoxicity which would greatly increase the incidence of chronic graft dysfunction. Another side-effect of CNI immunosuppressants is allograft fibrosis, caused by the up-regulation of transforming growth factor beta (TGF-β) by the CNI. Although TGF-β does possess immunosuppressive activity, it leads to tissue fibrosis by inducing the deposition of matrix protein. Some clinical trials had found out that there was an increased in the tremor events, cardiomyopathy and de novo post-transplantation diabetes mellitus among patients who received tacrolimus-based immunosuppression regimen,9, 10 whereas patients who received the immunosuppression regimen containing ciclosporin microemulsion were found to have suffered from an increased in hyperlipidaemia, hirsutism, gingivitis and nephrotoxicity.
Induction therapy is started a few weeks before patients undergoing the kidney transplantation surgery or is given immediately to patients after the transplantation surgery for a duration of 1-2 weeks. The aims of the induction therapy is to decrease the sensitivity of of the immune system towards the allogeneic graft transplanted.10 Basiliximab is a monoclonal anti-interleukin 2 receptor antibody which capables of expressing its immnunosuppressive activity by inhibiting the proliferation of T-lymphocyte. According to BNF, Basiliximab is given to patients 20mg intravenously 1-2 hours before surgery and 20mg 4 days postpoperative. It is often used in combination with CNI during the initial therapy. This combination therapy enables a lower dose of CNI to be given to patients but same desired clinical outcomes obtained. It is of utmost important for the patients to receive as low dose as possible of CNI immediately after kidney transplatation as the graft is very vulnerable to the nephrotoxic effect of CNI, which may lead to failure in the function of the graft transplanted.
Patients receive initial therapy once they had undergone kidney transplantation and treatment usually lasts for 3 months and thereafter it would be changed to maintenance therapy. The initial therapy are usually composed of either dual or triple therapy with CNI-based regimen, although sometimes the CNI ciclosporine might be used as monotherapy.9, 10 Example of the dual therapy being used in the practice is ciclosporine-prednisolone (corticosteroids) combination therapy, whereas the triple therapy consists of a CNI ciclosporine based regimen( in which ciclosporine could be substituted by tacrolimus), in combination with prednisolone and azathioprine. Occasionally a combination of Basiliximab, CNI ciclosporine and prednisolone may be given to patients. According to BNF, the dose of azathioprine used in the triple therapy is 1-2.5mg/kg daily and adjusted according to patients’ responses;9 the dose for prednisolone is given initially 20mg daily, but is then reduced gradually over 3-6 months to 5mg or could be withdrawn completely from the patients; whereas the dose for ciclosporin is recommended to be 2-6mg/kg daily or lower when being given simultaneously with corticosteroids (prednisolone) and the dose is adjusted according to patient’s renal function as well as their blood-ciclosporine concentration
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The maintenace therapy is usually started after 3 months of the transplantation surgery and its treatment is same with the initial therapy, but all the doses of the immunosuppressants are much lower compared to that of the initial therapy. The dose of the immunosuppressants are reduced during the maintenance therapy as the the risk of transplanted graft rejection by the patients’ immune system is greatly decreased compared to the initial postoperative period.10 In addition, the dosage of the immunosuppressants are reduced in order to minimise the side-effects that suffered by the patients, for instance nephrotoxicity, to preserve the well function of the transplanted graft and prolong the survival period of the graft as well as patients’ life expectancy.
Sometimes patients may develop acute kidney rejection due to a sudden decrease in the immunosuppressive activity by the immunosuppressants, as a consequence of drug interactions or increased clearance from patients’ bodies. Acute rejection is manifested by a decreased in urine output, an increased in creatinine level in urine, oedema and fever.10 It is very important to counteract the acute rejection in order to reserve graft function and thus the survival of the graft. The acute rejection is usually managed by increasing abruptly the dose of the corticosteroids in the triple combination therapy prescribed to patients during the maintenance therapy10, and the route of administration of corticosteroids is intravenously due to its faster onset of action and avoidance of first-pass metabolism. However some patients with acute rejection may fail to response to the increased dose of corticosteroids treatment, which the acute rejection is regarded as ‘corticosteroid-resistant acute rejection’. Polyclonal antibodies antihymocyte immunoglobulin (ATG), antilymphocyte immunoglobulin (ALG) and monoclonal antibody muromonab-CD3 are choice of treatment in the case of corticosteroid-resistant acute rejection in United States,10 however only antimyocyte immunoglobulin ATG is licensed for used in Uk. On the other hand, switching of CNI ciclosporin to a high dose of tacrolimus may also help to resolve the corticosteroid-resistant acute rejection. The acute rejection is preventable by prophylaxis treatment , a triple therapy consists of mycophenolate mofetil (an antiproliferative agent, which may also been used in initial and maintenance therapy), ciclosporin and corticosteroids. Mycophenolate mofetil 1g (twice daily) is given orally to patients no longer than 72 hours after undergoing transplantation surgery.
Every kidney transplanted recipient patient should receive an induction therapy with either Basiliximab or antihymocyte immunoglobulin ATG before or after the transplantation surgery. There are consistent evidences from studies proved that induction therapy could significantly reduce the risk of acute rejection in patients received induction therapy in addition to the dual or triple combination therapy.12 Although ATG was found to be more effective than Basiliximab in prevention of the incidence of acute rejection of graft, it is associated with a higher risk of CMV infection and non-melanoma skin cancer, meanwhile it does not improve the long term graft surval rate.12 Thus Basiliximab is recommended to be used in patients at low immunological risk, whereas those patients at a high immunological risk may need to take antihymocyte immunoglobulin ATG during induction therapy. In addition, Alemtuzumab would be the choice of treatment for those patients received kidney graft from a deceased-donor.
In this case the 46 year old female patient is highly recommended to receive a triple therapy consists of a CNI ciclosporine based regimen(either ciclosporine or tacrolimus), in combination with prednisolone and mycophenolate mofetil during initial therapy. Occasionally a combination therapy of CNI ciclosporine, prednisolone and basiliximab; or CNI ciclosporin, prednisolone and azathioprine might also be a choice for kidney recipient patients. Ciclosporin although is used as monotherapy in some patients, it is not encouraged, as a high dose of ciclosporin is required to be administered to patients, which would put patients at higher risk of suffering from nephrotoxicity and thus a reduced graft survival period. Studies proved the immunosuppressive activity of tacrolimus is superior compared to ciclosporin as tacrolimus could also exhibit immunosuppressive activities which were not seen with ciclosporin, for example its inhibition on IL-2 induced IL-5 production by human CD4+ T cells, and IL-2 and IL-7 which stimulate T-cell proliferation. The higher potency of tacrolimus in immunosuppression than cyclosporine was proved by its ability to be used as mono therapy to overcome the corticosteroid-resistant acute rejection in patients treated with ciclosporine based regimen. Moreover, side effects of CNI such as hypertension, hirsutism, gum hypertrophy and hyperlipidaemia are less likely to occur among tacrolimus-treated patient groups. This is a very important benefit for the 46 year old female patient, who cares more about her physical appearance and is at risk of developing cardiovascular disease after her menopaused a few years later due to changes in post-menopause lipid metabolism. Tacrolimus is also more cost-effective than ciclosporin. Once daily dosing regimen of tacrolimus is likely to aid patient’s compliance to the immunosuppression treatment. Studies showed patients received tacrolimus /azathioprine dual therapy are at lower risk of suffering from acute rejection that those received cyclosporine /azathioprine and the risk of acute rejection is further reduced in patients received tacrolimus/ mycophenolate mofetil dual therapy. Patients’ survival rate is the highest with tacrolimus/ mycophenolate mofetil dual therapy; followed by tacrolimus /azathioprine dual therapy, and then cyclosporine /azathioprine dual therapy. During the first three months post-operative, the risk of graft rejection by the recipient patients is the highest, thus corticosteroids, prednisolone is often given to her as a triple therapy combining immunosuppressive agents tacrolimus, mycophenolate mofetil and prednisolone, to synergise the immunosuppressive activities by tacrolimus and mycophenolate mofetil while at the same time reducing their required dose, thus minimizing side effects suffered by her. However the dose of prednisolone is either gradually decreased to as low as possible according to her requirement or withdrawn after three months of its treatment, due to its adverse effects such as hypertension, hyperlipidaemia and diabetes. Moreover the patient is about at her age of menopause, she should not take corticosteroid for long term as this would increase her risk of getting osteoporosis. If female patient is severely intolerance to the triple therapy – CNI based regimen due to nephrotoxicity, a combination therapy of ciclosporin, prednisolone and sirolimus (a mammalian target of rapamycin inhibitor) may be a treatment choice. The combination therapy mentioned is advised to be initiated atleast for two months before attempting to withdraw ciclosporin from the regimen by gradually decreasing the dose of ciclosporin. If the female patient responded well to the withdrawal of ciclosporin, then she may take only sirolimus and corticosteroids in her future life-long treatment. Studies reported possible of the capability of sirolimus to prevent the incidence of chronic rejection. However, if ciclosporin withdrawal attempt failed over three months of the concomitant use of ciclosporin and sirolimus, the lowest possible dose of ciclosporin in combination of prednisolone and sirolimus should be given to the patient, as significant increase in serum creatinine level was observed among patients who received concomitant therapy of sirolimus and ciclosporin.17 Subsequently the patient should stop taking sirolimus whenever possible.
Aspirin 75 mg daily could be given to patient in prophylaxis of cardiovascular disease. Avoidance of smoking and grape juice is vital in maintaining therapeutic level of CNI as they would decrease CNI’s bioavailability by increasing its clearance. The patient should not try to conceive a baby until the subsequent year after transplantation surgery and her graft function has been stabilised. Due to teratogenicity of Sirolimus, if she is on that medication, she should discuss with GP to sort out an appropriate substitute drug and she should still continue contraception for 12 weeks after she had discontinued taking Sirolimus. She should minimise her exposure to sunlight as CNI immunosuppression treatment would increase her risk of getting non-melanoma skin cancer. Additionally she should have cervical smear test done whenever she attends her routine check-ups and self-examine her own breasts every month to detect any malignancy. She should also receive vaccination against influenza every year. She should maintain personal hygiene and drink cranberry juice to prevent urinary tract infection incidence. She should eat a low salt and fat content but high calcium and vitamin D containing food to manage the side effects of immunosuppressive drugs such as hypertension, hyperlipidaemia and osteoporosis.
In conclusion, the triple combination therapy consisting of tacrolimus, prednisolone(for short term use) and mycophenolate mofetil is the best choice of treatment for this 46 year old female patient as it is a safer, more cost-effective and efficacious treatment compared to ciclosporin-based regimen as evidenced by the discussion in previous paragraphs. However, the choice of treatment is much dependent on the patient medical condition at a particular time which is changeable from time to time, patient’s tolerability towards the side-effects or adverse effects of the CNI in addition to the preference of the medication choice in practice in different hospitals. Closely monitoring of patients’ response to immunosuppression therapy by measuring through levels of different immunosuppressive agents; blood pressure; serum creatinine level; electrolytes, LFT, FBC, random glucose and cholesterol during every single routine check-ups is essential in determination of the dosage regimen of each immunosuppressive agents for each patient; the well function of graft; and detection of relative risk of acute and chronic rejection of the graft.
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