Our scenario is a 64 year old male patient with a liver transplant who requires an antiproliferative immunosuppressant. Firstly, we will discuss the procedure in general with some evidence of survival rates statistic from other studies. Then we will look into the complications that might occur after the liver transplant and the best treatment options available for this particular patient.
1.0.2 Liver transplant
Strazl and Calne established the fundamental techniques to successfully perform a liver transplant surgery 15 years ago. Due to its added potential in curing patients with chronic liver disease, liver transplant has been rapidly progressing over the last two decades. Currently, it is an established therapy for patients who suffer from irreversible end-stage liver failure. The procedure is commonly considered in patients with chronic liver disease, malignancy, inborn errors metabolism and fulminant liver failure (1).
Studies found that the annual liver transplant rate in the Europe is 5500 cases whereas in the United States there are 3925 cases, and the paediatric age group contributes 5% of the overall transplant rate in Europe (2,3). A study done by Jain A et al. showed that the survival rate was the lowest in patients who are more than 60 years old in comparison to the survival rates for infants, children and adults with the age range of below 2 year old, 3 year old to 18 year old and 16 year old to 60 year old respectively. The statistics for the 1, 5, 10, 15 and 18 years survival rates are summarised in the table 1. This study also showed that the cases of mortality during the follow-up period was 40.8% with infection being the major cause with 28.4%, followed by recurrent or de novo cancers (11.6%), cardiovascular (8.3%) and respiratory-related cases (7.0%) (4).
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3 -18 years
16 - 60 years
Table 1 : Survival rate in post liver transplant patients of different age group
1.0.3 Complication with liver transplant
Regardless of the high post-transplant survival rate, liver transplant still poses a risk to the patients. Complications of liver transplant can be either immediate, long term or both. These complications usually occur as a result of pre-existing disease, surgical procedures and the response of the immune system against grafted organ.
Immediate complications in liver transplant include technical and medical complications, liver graft dysfunction, rejection and infections. Statistics had revealed that technical complications contribute an average of 26% of the overall immediate complications experienced by patients who undergo liver transplant. One of the most common technical complications in liver transplant is of arterial in origin, particularly thrombosis of hepatic artery which has the highest prevalence ranging from 1.5 to 25%. Others include biliary diseases and portal vein thrombosis, a very rare condition with an overall prevalence of approximately 2% to 3% (5,6). Medical complications include the side effect of immunosuppressive drugs such as changes renal function, haemodynamic related problems, and affected neurological states (5,6). Primary graft dysfunction is one of the most critical conditions that can lead to death or retrasplantation and the incidence of it occurring is approximately 5-10% (5,6). Rejection is a major barrier in transplantation. Immediate rejection can be either hyperacute or acute. Hyperacute rejection is antibody and complement mediated and it can occur within minutes to hours. On the other hand, acute rejection happens over a period of days to months. Another life threatening condition is superadded infections. Statistics showed that the number of patients who have at least one infective complication exceed half of liver transplant population and it contributes to more than 50% of the rate of mortality in liver transplant receivers (5,6).
Long term complications
Patients with liver transplant are prone to develop chronic rejection that will only show symptoms 6 months after the transplant. Patients with chronic rejection will present with a loss of small bile duct and obliterative angiopathy on their biopsy results. Usage of immunosuppressive agents may also show long term complications such as, chronic renal failure, osteopenia, diabetes mellitus (a prevalence of 4% to 20%) and atrial hypertension ( incidence rates ranging from 50-70%) in the first few months after the transplant. . Patient with a liver transplant are also prone to develop obesity with prevalence varying from 15% to 40%. In fact, there were also cases of malignancy being reported. The most common cancer is the De novo malignancy which shows an occurrence of 5% to 15% and the prevalence doubled in patient with cancer. (5,6)
1.0.4 Cost of graph failure and rejection
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Immunosuppressive regimens after liver transplantation can be very costly as one pack of antiproliferative immunosuppressant can cost up to £200 (7). If inadequate immunosuppressive agents were given to the patient, this will lead to rejection or graft failure. A study that was done by Martin et al in 1998 showed that an average of £16,561 is needed for one episode of rejection in liver transplant. This amount covers the cost for diagnosis, treatment of rejection, complication related to rejection, outpatient medications and home therapy. (8)
2.0 Current immunosuppressive strategies and regimens
The immunosuppressant therapy is the cornerstone of medicine for patients with liver transplant. This regimen aims to maintain the balance between the drug efficacy, drug toxicity and cost effectiveness. The drug efficacy is assessed based on the occurrence of graft rejection and survival rate. The current immunosuppressant regimen includes two phases: the induction phase and the maintenance phase. The Induction phase is a short term therapy and it commences during the perioperative period in order to thwart off rejection episodes. Upon completion of induction, patients will be introduced to the maintenance phase regime which is a long-term treatment. Maintenance therapy targets to minimize the usage of immunosuppressant that is sufficient to prevent rejection while ensuring that the host immune system remains competent against infections and development of tumour (9,10). The standard immunosuppressant regime is shown in figure 1. In most of the transplantation centres, the combination of corticosteroids (hydrocortisone at induction and then tapering steroid dose), calcineurin inhibitor (CNI) and an antiproliferative immunosuppressant is used as the standard therapy. Another possible option is the dual regimen of steroid and calcineurin CNI (11). Some of the patients were also started on triple therapy as the initial course before continuing with a monotherapy of calcineurin inhibitor (12,13). Since CNI, steroid and antiproliferative immunosuppressant are the most commonly used immunosuppressant, we will discuss in depth on these 3 types of immunosuppresants in this section.
Figure 1: Proposed standard regimen of immunosuppression after liver transplantation with the right box indicating the modification that should be considered in specific circumstances. [adapted from (14)]
The introduction of calcineurin inhibitors (CNIs) in 1970s had shed some light on patients' lives. CNIs became the backbone immunosuppressant for post liver transplantation immunosuppressant regime and the most commonly used CNIs are cyclosporine (Csa) and tacrolimus (Tac). The introduction of both Tacrolimus and Csa had improved the survival rate of the patient and graft and reduces the incidence of post transplantation acute rejection significantly (15). However due to the wide array of side effects that were cause by the usage of CNI such as, CNI induced chronic renal failure with arterial hypertension (the main cause of morbidity and mortality after liver transplantation), researches were determined to explore if avoidance of CNIs usage can be employed. The related adverse effects and clinical evidences of both drugs are shown in table 2.
O'Gray et al : Tacrolimus showed more benefits for adults with post liver transplant in terms of freedom from graft loss and immunological failure. There was significant difference between Csa and tacrolimus but the freedom from death or retransplantation were not statistical significance (relative risk 0.79; 95% Confidence interval CI 0.62-1.02; P = .065). (16)
Ojo et al. :Development of chronic renal failure in patients with nonrenal transplant within 5 years post transplant was up to 21% and prevalence of renal dysfunction after 15 years of liver transplantion was 18.1%. Renal dysfunction was directly associated with CNIs usage. (17)
Fisher et al:demonstrated that 4% of patients who survived the transplantation after a year developed chronic renal dysfunction secondary to CNI usage and 48% of them advanced to end stage renal failure and 44 died. (Fisher RA, Ham JM, Marcos A, et al: A t prospective randomized trial of mycophenolate mofetil with neoral or tacrolimus after.(18)
Wiesner RH. :Cumulative 5-year patient and graft survival rates for the patient on tacrolimus (79.0%, 71.8%) were higher than cyclosporine (73.1%, 66.4%). Half-life survival for tacrolimus-treated patients was longer (25.1+/-5.1 years versus 15.2+/-2.5 years; P=0.049) and greater improvement of hepatitis C-positive patients who were tacrolimus was also observed for (Tac:78.9%,Csa:60.5%; P=0.041). (19)
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Table 2 : Summary of side effects and clinical outcomes of CNIs
Corticosteroids are the most extensively used non-CNI drugs in liver transplant. Steroids are usually combined with the CNIs for the maintenance immunosuppressant regimen in order to prevent rejection episodes (14). However, due to the side effects exhibited by corticosteroid such as hyperglycemia, cushinoid syndrome, ulcers, myopathy, osteoporosis, fluid retention, cataracts hypertension, mental status changes, lipid abnormalities, and impaired wound healing, the avoidance of corticosteroid usage is favourable. A prospective randomized double blinded study by Moench and colleagues demonstrated that the survival rate was equivalent for both steroid and placebo group with 88% and 85% surviral respectively. In this study, the subjects were randomized to receive either a steroid or placebo on day 14 after liver transplant in combination with tacrolimus. (20). Consistent with this, a prospective randomised study by Vivarelli M et.al showed that the liver graft survival is dose related and the frequency of reccurence diseases was reduced when the dose of prednisolone was tapered down slowly (21)
Azathioprine is one of the earliest antiproliferative immunosuppressant used in the treatment of liver transplant. Studies has shown that the usage of azathioprine is usually well tolerated if the dose falls in the range of 1·5 to 2·0 mg/kg/day and it is effective in preventing rejection episodes. However, azathioprine dose not have significant effects on established immune response (22). Regardless of insufficient randomized controlled trials that evaluate the clinical efficacy of azathioprine in liver transplant, azathioprine remains as the conventional primary antiproliferative immunosuppression. However the usage of azathioprine was significantly reduced over time primarily due to the side effects posted by this drug and the introduction of the newer, less toxic antiproliferative immunosuppression agents. (22,13). The new antiproliferative immunosuppressant is mycophenolate compounds which come in two forms; mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (23). Mycophenolate compounds are very safe as their actions on the T cells and B cells do not affect the affecting bone marrow and parenchymal cells, hence it does not exhibit nephrotoxicity and neurotoxicity (15). Various animal models were used to illustrate MMF efficacy and studies showed that it reduces and slows down the onset of chronic rejection(24,25). Recent reports showed more than 50% of the transplant centres in the U.S have given their patients MMF within the first year after liver transplantation(26). Table 3 summarises the side effects and the studies done on these 2 drugs. Studies on antiproliferative agents were performed as cyclosporine-a-based theraphy or tacrolimus-based therapy.
Nausea, vomiting, diarrhea
Connell WRdemonstrated that 5% of the patient showed sign of bone marrow toxicity, 3.8% suffered from leukopenia, with 2 fatal cases due to sepsis and several of them developed pneumonia and mild mild upper respiratory infection only. (27)
Jain et al.:A randomized cotrolled study in 2 groups of primary adult liver transplant recipients that were on either tacrolimus and steroids or tacrolimus, steroids and MMF. The study showed that lower episodes of acute cellular rejection we reported by patients who were on MMF, besides showing improvement in patient and graft survival and renal function. Patients on MMF also required lesser amount of maintenance steroids and calcineurin inhibitors dosage could be reduced in patients with significant renal dysfunction(28)
Pulido LB et alsuggested that MMF monotherapy improved 70% of the renal dysfunction cases in 6 months and 69.6% in 12 months with the reduction of serum creatinine level from 1.63 mg/dL to 1.48 mg/dL whereas the is no change in the serum creatinine value in patients with normal renal function. The study also showed that MMF monotherapy was well tolerated and safe as it did not show any increase the risks of graft rejection or loss. (29)
Nausea, vomiting, diarrhea
Bone marrow suppression
Table 3 : Summary of side effects and clinical outcomes of antiproliferative immunosuppressant
3.0 Recommendation of therapy
Immunosuppressant therapy should be tailored according to patient's needs and conditions in order to reduce the rates of rejection, enhance graft and patient survival, and minimize the immunosuppressant-related toxicity. After reviewing the antiproliferative immunosuppressants available for current immunosuppression regimen, I would recommend the usage of MMF and Tacrolimus (a CNI) in combination with a steroid (which will be tapered gradually and stopped after 6 months). This combination is recommended instead over MMF monotherapy regimen because studies had shown that the usage of MMF as a monotherapy in liver transplantation will lead to undesirably high incidence of acute and severe chronic cellular rejection, severe steroid-resistant rejection and a subsequent need for retransplantation (30,31). MMF is the drug of choice instead of azathioprine because it is safer and it is more effective in preventing graft rejection in comparison to Azathioprine. The effectiveness of MMF was interpreted from the rate of 'patient and graft survival' after liver transplantation and episodes of liver rejection. Besides being more effective, MMF has a better safety profile as it produces fewer side effects than azathioprine. However, there are no studies comparing both antiproliferative immunosuppressants with a placebo-control-group because of the ethical issues involved as we are aware that it is life threatening to prescribe merely antiproliferative immunosuppressant or placebo to the patient with liver transplant. Therefore, concomitant use of other immunosuppressant was manipulated to compare the effectiveness of these two drugs and the studies are summarised in table 6. In this case, the CNI chosen was tacrolimus it safer and more efficacious than cyclosporine as the long term immunosuppressant after transplantation. (32,33)
Fischer L et al.
Lymphocyte antibodies Corticosteroid cyclosporine A
The number acute rejection episodes was lower in MMF treated group in comparison to azathioprine group with incidence of 40.6% and 19.4% respectively and P value of 0.06. However patient survival rate showed no significant different between the two groups ( MMF : 90.3% and AZA: 87.5%). The occurrence of thrombopenia was significantly lower in MMFtreated patients (MMF: 19.4% versus AZA: 146.9%, P <0.05). Similarly, leukopeniatrend was also lower in the MMF arm (MMF: 6.5% versus AZA: 18.8%, P = 0.12) but it was not significant. Patient treated with MMF in contrast exhibited gastrointestinal side effect more often than azathioprine treated patient, but they were always mild.(34)
Sterneck M et al
Cyclosporine and steroid
There was a significant reduction of acute rejection and graft loss in MMF(1.5 g b.d.) group in comparison to AZA (1-2 mg/kg/day) where MMF treated group showed 38.5% whereas AZA treated group showed 47.7% with p value of 0.025. However, there was no signiï¬cantly different in 1-year patient and graft survival rates for both group with MMF 88.8% and 85.3% versus AZA 87.1% and 85.4%, respectively. (35)
Table 4: Summarised studies on the effectiveness of azathioprine versus MMF
Although the triple therapy of Tacrolimus, MMF and steroid was proven to be more effective in preventing acute rejection, many studies had demonstrated that CNIs can give rise to numerous adverse effects (37,38,39). The most common CNI induced side effects experience by the patient is nephrotoxicity and this has been shown in many studies in table 3. Given that patient is an elderly 64 year old gentleman, the chances of him developing renal dysfunction is higher as age and gender are risk factors of renal dysfunction. A study by Jungers P et al. demonstrated that annually, the incidence of renal failure in males had doubled compared to females up to 75 years and, incidence of renal failure in those who are 75 year old and above is three times higher (40). Considering that this particular patient is at high risk of developing renal dysfunction after the commencement of CNI, MMF is therefore recommended to the patient instead of azathioprine. Moreover, studies had demonstrated that MMF was proven to be able to limit the side effect associated with CNI by allowing the reduction in CNI dosage amount or complete withdrawal of CNI (14). In addition, MMF is also capable of reversing the nephrotoxicity secondary to CNI which makes it a better choice of antiproliferative immunosuppresant. Table 5 summarised some of the studies that showed the use of MMF monotherapy or a combination with a low dose of CNI is more favourable in controlling and reversing CNI associated nephrotoxicity.
Schlitt et al. (41)
Replacement of CNI to MMF improves mean serum creatinine with the reduction of 44·4 μmol/L in MMF group compared with 3·1 (14·3) μmol/L in CNI group. Moreover, systolic and diastolic blood pressure, and serum uric acid decreased significantly in the MMF group but not in the CNI group with mean difference between groups of 10·8 mm Hg.
Jain et al. (42)
The introduction of MMF and reduction of tacrolimus dose by 30-50% resulted in overall mean serum creatinine reduction from 2.5 to 1.9 mg/dl at 6 months but increased to 2.2 mg/dl at 18 to 24 months. Renal function then remained stable for 72 months and 58% of patients showed sustained improvement in renal function.
Jiménez-Pérez M et al. (43)
CNI therapy was converted to monotherapy with MMF due to adverse events associated with CNIs and there was a progressive decrease in creatinine during the initial months. Compared with baseline levels, the differences at 3 and 6 months of monotherapy were significant (P = 0 .001) which remains so throughout the follow-up period. Renal function improved in 88% of patients and normalized in 60% of patients.
Table 5 : Summarised studies that show MMF monotherapy or combination with low dose of CNI is favourable in controlling and reversing CNI associated nephrotoxicity
Despite the fact that MMF-based regimens is more costly than azathioprine-based regimens in liver transplant recipients as shown in table 8, the MMF-based regimen is still desired due to the superiority of MMF over azathioprine. In view of the fact that MMF is statistically significant in preventing the incidence of acute rejection, this will potentially result in the cut down of the cost on rejection-related treatment as there will be lower number of rejection episodes, decrease in the length of hospitalization and ultimately reduction in graft failure incidence. Therefore, the recommendation of using MMF instead of azathioprine is favourable as patients treated with MMF will be likely to have lower treatment costs in comparison to patients who are on azathioprine. MMF-based regimen is hence more cost-effective than azathioprine-based regimen. Therefore, taking into account patient's condition, the effectiveness, safety profile and cost of MMF over azathioprine in combating acute and chronic rejection episodes, MMF is the best choice of antiproliferative immunosuppressant in this particular patient.
Cost/year (US dollars)
Tac-+ Aza + St.
Tac-+ MMF-- St.
2500.00 / year
Table 6: Cost of immunosuppressive therapy in organ transplantation (44)