Every year, statistics showed that there is a 7-10 increase of dialysis patients and the need for kidney transplant are expected to rise throughout the decade (NICE, 2004). Kidney transplantation is a surgical operation undergo by patients when both kidneys fail to perform its duty. Besides kidney transplantation, patients may opt for hemodialysis or peritoneal dialysis. However, patient must go through thorough examination before transplantation can take place and the search for a suitable kidney donor is not easy. Kidney transplant can come from either living donors or non-living donors, and both have their own pros and cons. When compared to the general population, kidney transplant patients have higher mortality rates although lately, immunosuppressive drugs were found to contribute to a 95 improvement in the short-term survival rate of renal transplant recipients (Roberto, 2009). The usual causes of increased mortality rates among renal transplant patients are cardiovascular disease, malignancies and infections. These problems are likely to be indirectly associated with the use of calcineurin inhibitors and anti-proliferative agents. A multivariate survival analysis performed by Gill et al (2002) concluded that these non-immunologic factors (drug use, cardiac problems, diabetes, elderly) were responsible for the increased mortality rate among kidney transplant patients. Hyperlipidaemia, diabetes mellitus, hypertension, and increased weight gain associated with side effects of medications, are known to predispose transplant patients to all risk factors for cardiovascular diseases. Rischen-Vos et al. (1992) specifically conducted a 10 years study on the mortality and morbidity rates, comparing both diabetic and non-diabetic patients respectively. Cerebrovascular incidence (23 vs 3), peripheral vascular disease (31 vs 3) and infections (1.9 vs 1.2), which were significantly higher after transplantation, proved that mortality and morbidity rates were increased especially in diabetic patients.
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The main benefit of kidney transplantation for patients with end stage kidney failure (ESRF) is an improvement in the quality of their life and increased rehabilitation. They are less restricted in their fluid and dietary intake, and need not endure the pain of going through dialysis. Generally, a marked increase of survival is often seen in kidney transplant recipients when compared with both haemodialysis and peritoneal dialysis (Vollmer et. al, 1983). Another study was performed by Mazzuchi et. al. (1999), comparing the number of survival between the haemodialysis patients with renal transplantation in Uruguay and it was found that in 10 years, the survival was significantly greater in patients with renal transplantation (78.8 vs 39.8). Nevertheless, when co-morbid factors were taken into account, there were no difference between both groups in non-diabetic patients (P=0.2312); while in diabetic patients, kidney transplants gave increased survival rate than haemodialysis (P=0.0168).
The downside of renal transplantation includes rejection, infections, and complications post-operation, such as bleeding, thrombosis, urinary leaks and oliguria. Patients must be monitored extremely closely after a kidney transplant. Rejections occur commonly and up to 70 of recipients encounter this during the first few weeks after transplantation (Kidney patient guide, 2009). This is mainly due to the human's immune system, which plays a role in guarding the body from foreign matter. Since kidney implant is regarded as a foreign matter to the body, the defense system will automatically try to combat the invader. Acute rejection occurs when inflammation response develops, followed by failure of tissues to repair themselves. This may take place within 24 hours or over a period of days and weeks after organ transplantation. Therefore, it is a must for all kidney transplant patients to take immunosuppressant drugs in order to minimize the chances of rejection and allowing tissue repair to progress.
2.0 The use of Calcineurin Inhibitors
Take an example of a scenario, where a 46 years old female patient with a kidney transplant requires calcineurin inhibitors. The calcineurin inhibitors are the most prescribed immunosuppressant medications and certain patients may require more than one immunosuppressants to prevent rejection. In addition to the regimen are steroids and a third drug, such as mycophenolate or azathioprine (Longmore et. al, 2007). The dose of each drug varies between individuals and they may take up to several months to be stabilized on the drug. After a kidney transplant, patients are usually required to take three types of medications, which includes the immunosuppressants, medicines used to reduce the side effects of the immunosuppression drugs, and also the antihypertensives and lipid-regulating drugs.
The activation of T-lymphocytes comprises of two phases and is associated mainly with the intracellular processes catalysed by calcineurin. When calcineurin inhibitors are administered, they act at the first phase of T-cell activation, by binding to intracellular proteins, known as immunophilins, thus blocking the lymphocyte response pathway. As a result, there is a decreased in both the production rate of interleukin-2 (IL-2) and proliferation of T-cells (Pillans, 2006). The most commonly prescribed calcineurin inhibitors are either the ciclosporin or tacrolimus. Ciclosporin was introduced during the 1980s, whereas tacrolimus came about as an alternative only in the 1990s (Hong & Kahan, 2000) For over two decades, ciclosporin has been approved as the primary immunosuppresant in organ transplantation and prevention of graft rejection. Ciclosporin exerts its action by binding to the cytosolic immunophillin, known as cyclophilin. The complex formed inhibits the phosphatase activity of calcineurin and hence, preventing calcineurin-mediated dephosphorylation (Pillans, 2006). Since ciclosporin is a substrate for cytochrome P450 3A4 and P-glycoprotein, concurrent administration of drugs influenced by these enzymes may influenced the absorption and elimination of ciclosporin. It is important to monitor the patient's kidney function as adjustment of the dose may be required if there is an increased in serum creatinine and urea during the first few weeks of treatment. Common adverse effects associated with ciclosporin includes nephrotoxicity, hypertension, tremor, hypertrichosis, gingival hyperplasia, and hyperlipidaemia (BNF, 2009)
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Tacrolimus is another calcineurin inhibitor, which functions also as a macrolide antibiotic. It acts by impairing the gene expression in targeted cells, which occurs through the binding of tacrolimus to the immunophilin, FK506 binding protein (FKBP). This leads to the inhibition of calcineurin phosphatase and calcium-dependent events. The drug also inhibits T cells proliferation by enhancing the expression of the growth factor beta-1 gene (Thomson et al, 1995). Although both ciclosporin and tacrolimus antagonize calcineurin activity and calcium-dependent T cells activation, clinical and experimental studies have shown that they do not have similar immunosuppressive effects. A study conducted by Rostaing et al. (1999) among stable renal allograft recipients, showed that tacrolimus had higher efficacy in reducing the production of IL-2-producing T cells, when compared with ciclosporin. It is evident that tacrolimus not only affects ciclosporin-sensitive pathways, but also the ciclosporin-insensitive pathways. The major differences between both these drugs were noted by the ability of tacrolimus monotherapy to reverse the steroid-resistant allograft rejection episodes, and the failure of ciclosporin in treating allograft rejection (Almavi & Melemedjian, 2000).
Tacrolimus has a narrow therapeutic index and it is prone to cause serious medication errors if not prescribed carefully. This drug is available in two different formulations (PrografÂ® & AdvagraftÂ®) and both are not identical. The Committee of Safety and Medicines (CSM) have warned that patients must be monitored carefully by echocardiography specifically for hypertrophic changes (BNF, 2009). Hyperlipidaemia, hypertrichosis and gingival hypertrophy seemed to be less of a problem, whereas diabetes melittus and cardiomyopathy is associated with the use of this drug. There is evidence that the incidence of neurotoxicity was much greater for tacrolimus. Case reports by Scheel et. al. (2001) concluded that tacrolimus-based therapies had higher number of neurologic complications, such as anxiety, insomnia, paraesthesia and dizziness, compared to ciclosporins. Another systematic review was undertaken by Webster et al (2005) to compare the effects of tacrolimus and ciclosporin as initial treatment for kidney transplant patients. Tacrolimus treated patients were found to have lesser incidence of acute rejection and improved graft survival. However, there were an increased in number of patients reported with diabetes mellitus, neuropathy and gastrointestinal disorders when compared with ciclosporin. It is well documented that tacrolimus is more superior to ciclosporin in many ways, but it is very important to weigh and consider the benefits and risks of each treatment before deciding on the best choice of drug for the individual patient.
3.0 Treatment options - Advantages and Disadvantages
Firstly, there is a list of treatment options available for this patient. Immunosuppresion therapy itself is usually a combination of a calcineurin inhibitor an antiproliferative agent and a corticosteroid. Some treatment centres may adopt the policy of monotherapy, which begins with a calcineurin inhibitor, adding on the following two drugs if necessary (NICE, 2004). Most transplant centres currently use the triple therapy combination of Tacrolimus, Mycophenolate Mofetil and Prednisolone (Kadambi, 2010). However, it is important to note the patient's medical history before deciding on the best choice of calcineurin inhibitors. As an example, ciclosporin would be a better choice compared to tacrolimus in a diabetic patient, as studies have found that tacrolimus doubles the risk of diabetes mellitus requiring (Webster et al, 2005). Patients also have the tendency to forget to take their medications or stop taking them due to side effects. Rejection of kidney transplantation is often due to patient's non-adherance to medication. Chisholm et al (2004) had conducted a study to determine the difference between renal transplant patient's compliance to ciclosporin and tacrolimus. It was found that patient were more likely to comply with tacrolimus, compared to ciclosporin (63 vs. 33 with p < 0.05).
Besides the calcineurin inhibitors, sirolimus is a potent non-calcineurin inhibitor, which is licensed for the use in kidney transplant patients as prophylaxis of organ rejection. According to the BNF 2009, sirolimus is used initially with ciclosporin and corticosteroids for 2-3 months, then with corticosteroids only. Since ciclosporin increases the serum levels of sirolimus, it is advisable to give sirolimus 4 hours after ciclosporin. Both this drugs must be used with caution as they may cause renal toxicity when used concurrently for more than 3 months (Baxter, 2008). Sirolimus have a different mechanism of action from the calcineurin inhibitors. Although sirolimus and tacrolimus act on similar intracellular target, namely the FKBP12 protein, sirolimus interrupts at the second phase of T-cell activation by blocking the signal transduction pathway needed for progression from G1 to S phase (Abraham & Wiederrecht, 1996; Morelon et al, 2001). The major advantage of including sirolimus in the therapeutic regimen after renal transplantation over the calcineurin inhibitors is the absence of nephrotoxicity. A phase II randomized trials conducted by Groth et al (1999), comparing sirolimus-treated and ciclosporin-treated renal transplant recipients, showed that the sirolimus-treated patients have lower levels of serum creatinine after two years. Another randomized trial studied the potential use of sirolimus as base immunosuppressive therapy, in combination with an anti-proliferative agent and a steroid. Results comparing sirolimus and ciclosporin A suggested that the graft survival (92.5 vs 89.5), patient survival (97.5 vs 94.7), and occurrence of acute rejection episodes (7.5 vs 5.3) were not statistically different and the sirolimus group had better renal function after a year (Kreis et al, 2000). This means that the non-nephrotoxic sirolimus may possibly be a better option after all, replacing ciclosporin in the triple immunosuppression therapy. More clinical studies should be undertaken to justify this. The common side effects of sirolimus are diarrhoea, abdominal pain, pyrexia, hypercholesterolaemia, hypertriglyceridaemia, pneumonia and increase susceptibility to infection. Studies have shown that sirolimus-treated patients had higher percentage of hypertriglyceridaemia and hypercholesterolaemia, especially the first two month but not significantly different at the twelveth month, in comparison to the ciclosporin-treated groups (Kreis et al, 2000). Sirolimus is indeed a potent immunosuppressive agent and may well be an alternative to calcineurin inhibitors.
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The antiproliferative immunosuppressants currently employed are the azathioprine and mycophenolate mofetil. There is always a constant debate on which is the better choice but both have its advantages and disadvantages, and this certainly depends on the type of patient we are treating. Azathioprine is metabolized to 6-mercaptopurine, which inhibits purine synthesis, decreasing T-lymphocytes proliferation (Maltzman & Koretzky, 2003). Unlike azathiopurine, the prodrug mycophenolate mofetil is converted to mycophenolic acid, responsible for inhibiting the inosine monophosphate dehydrogenase (IMPDH) in the purine synthesis pathway. It has a more selective mode of action than azathioprine, as it specifically reduces the guanine nucleotide pools in T-lymphocytes (BNF, 2009; Ransom, 1995). Both these drugs should be taken with caution as they may cause bone marrow suppression. Patient is advised to report any signs of infection and unexplainable bruising or bleeding. Patients on long-term azathioprine with low enzyme thiopurine methyltransferase (TPMT) usually are at higher risk of myelosuppression. Several studies have been conducted to investigate the use of both drugs in renal transplant recipients. David et al (2005) compared the use of mycophenolate mofetil and azathioprine in diabetic renal transplant patients and the outcome showed decreased incidence of acute rejection, decreased risk of late acute rejection and cardiovascular death, and a lower malignancies in patients taking mycophenolate mofetil. Another study evaluated the safety and compared the side effects of mycophenolate mofetil versus azathioprine in renal transplant patients. Based on 6387 patients from 20 trials, there is a slight increased in gastrointestinal effects, hematologic events and tissue-invasive cytomegalovirus infections associated with the use of mycophenolate mofetil (Wang et al, 2004). However, a randomized trial conducted comparing the antirejection activity of both drugs with newer ciclosporin formulation showed that mycophenolate mofetil has no advantage over azathioprine in preventing acute rejections. In addition, the overall estimated cost of treatment for mycophenalate-based patients were â‚¬448 416 and for the azathioprine-based patients were â‚¬27 716 (Remuzzi et al, 2004). Since the cost of mycophenolate mofetil was fifteen times more expensive, azathioprine is likely to be more feasible in the standard immunosuppression regimens for kidney transplantation.
Prednisolone is a commonly used immunosuppressive agent post-kidney transplantation. Rejection is often due to inflammation and corticosteroids are usually given, with the aim of reducing inflammation (Peters, 2003). Patient is initially given high doses of prednisolone but may be decreased over time, by judging on the well being of the patient. Nevertheless, prednisolone presents to us its many side effects, such as diabetes, hypertension, osteoporosis, peptic ulceration and perforation, muscle wasting and weight gain (BNF, 2009). A survey conducted among kidney transplant patients had named prednisolone as the drug, which they most like to discontinue (Prasad et al, 2003). Although the use of prednisolone seemed beneficial, results from several studies have demonstrated the possibility of a prednisolone-free regimen. A five-years study performed by Matas et al (2005) among kidney transplant recipients on prednisolone-free regimen, reported to have found significantly lower rate of cataracts, post-transplant diabetes, avascular necrosis and fractures, while maintaining a good graft outcome. Another study also by Matas et al (2004) concluded that prednisolone-free recipients had better patient and graft survival without increased risk of acute or chronic rejection.
3.0 Recommendations and supporting evidences
Based on the NICE guidance (2004) recommendations, Basiliximab, a monoclonal antibody, which prevents the proliferation of T-lymphocytes, can be combined with a calcineurin inhibitor for induction therapy in the prophylaxis of organ rejection. It is usually given via intravenous injection and it should be restricted to specialist centres only. Emparan's et al (2003) had conducted many studies focusing on the cost-benefits of Baziliximab and although it is expensive, elderly patients were found to benefit from induction with basiliximab, leading to a decrease in the overall medical costs of transplantation. These patients also had better initial function with lesser complications after a year follow-up (Emparan et al, 2005). During an acute rejection, short courses of high-dose corticosteroids are usually the standard treatment but sometimes, the need for a stronger immunosuppression such as the antithymocyte immunoglobulin (ATG) may be necessary (NICE, 2004). However, they may be an increased tolerance of ATG due to pretreatment with intravenous corticosteroids and antihistamine, initiating the need for an antipyretic drug (BNF, 2009). High doses of tacrolimus may also be used to treat corticosteroid-resistant acute rejection. According to the NICE guidance, the use of mycophenolate mofetil should be confined to patients intolerable to calcineurin inhibitors or when there is a very high risk of nephrotoxicity, prohibiting the use of calcineurin inhibitors. Sirolimus should only be added into the regimen if there is a need to withdraw calcineurin inhibitor, due to intolerance. All kidney transplant patients are also recommended to take several other medications to decrease the risk of acquiring an infection as immunosuppressants greatly suppress the body's immune system (Aradhye, 2006). During the first few months after transplantation, patients are likely to be susceptible to infections by cytomegalovirus (CMV), which may be prevented by taking acyclovir. Co-trimazole can be prescribed to prevent pneumocystis carinii pneumonia (PCP). Patients having uncontrolled blood pressure or increased cholesterol levels are at risk of kidney damages. It is vital for these patients to receive antihypertensive agents and statins to prevent further damage (NHS Direct PIL, 2007). Therefore, the primary aim should be to reduce the risk factors involved with taking immunosuppressants, in order to improve graft survival in a long run.
In conclusion, having renal transplant is a lifelong commitment to patients and they must take the initiative to maintain a good kidney function. Many researches have been ongoing to develop and improve better use of immunosuppressant drugs for kidney transplant patients. Although kidney transplantation seemed risky, the outcome of a good kidney function significantly improves the lifestyle of these patients, providing them the chance of a normal and active life. Non-compliance to medications is the main reason for kidney rejection. By adhering to the correct usage of medications, we are not only able to minimize the chances of a rejection, but also decrease the incidence of adverse side effects. Patients should be well informed about the medications they are taking and how to take them correctly. Both the patient and the transplant care team must work hand-in-hand in order to achieve this goal. Prevention is better than cure. Early diagnosis with treatment of co-morbid and complications following transplantation can certainly improve the patient's survival.
Thus, a successful transplantation depends not only on the safe and effective use of post-transplant medications, but also the patient's diet, lifestyle and compliance to the medication.