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Our scenario is 64 year old male patient with a liver transplant who requires an antiproliferative immunosuppressant. Firstly, we will discuss a liver transplant 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 what are the best treatment options available for this particular patient.
1.0.2 Liver transplant
Strazl and Calne established the fundamental techniques to perform liver transplant successfully 15 years ago. Due to its potential in curing patients with chronic liver disease, liver transplant has been progressing rapidly over the last two decades. Currently, Liver transplant is an established therapy for patients who suffer from irreversible end-stage liver failure. Liver transplant procedure is commonly considered in patient 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 paediatric cases contribute 5% of the overall transplant rate in the 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 related cases (8.3%) and respiratory-related cases (7.0%) (4).
< 2 years
3 -18 years
16 - 60 years
> 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 posts complications to the patients. Complications in liver transplant can be either immediate or long term or both. These complications usually occur due to pre-existing disease, surgical procedures and the response of the immune system against grafted organ.
Immediate complications in liver transplant include technical complication, medical complication, liver graft dysfunction, rejection and infections. Statistic showed 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 arterial complications, particularly thrombosis of hepatic artery which has the highest prevalence ranging from 1.5 to 25%. Other technical complications include portal vein thrombosis which is very rare with an overall prevalence of approximately 2% to 3% and biliary complications (5,6). Medical complications include the side effect of immunosuppressive drugs such as heamodynamic complications, changes renal function and neurological state (5,6). Primary graft dysfunction is one of the most critical immediate complications occurs that will 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 occurs witin minutes to hours. Acute rejection however happens over a period of days to months. Another life threatening complication is the infections. Statistic showed that the number of patients who have at least one infections complications exceed half of liver transplant population and it contributes 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 transplantation. Patients with chronic rejection will show results which show the loss of small bile duct and obliterative angiopathy on their biopsy results. Similar immediate complications, some long term complications are also resulted from the usage of immunosuppressant agents such as chronic renal failure, osteopenia, diabetes mellitus that showed 4% to 20% of the patients develop diabetes mellitus subsequent to transplant and atrial hypertension with the prevalence ranging from 50-70% in the first few months after the transplant. . Patent with liver transplant will also prone to be obese with the prevalence varies from 15% to 40%. There were also cases of maglinancy reported by patient with liver transplant. The most common malignancy is the De novo malignancy which show occurrence between 5% to 15% in patients and the prevalence double in patient with cancer. (5,6)
1.0.4 Cost of graph failure and rejection
After transplantation, patient will be on the Immunosuppressive regimen which is very costly as one pack of antiproliferative immunosuppressant can cost up to £200 (7). If inadequate immunosuppressive agents were given to the patient, it 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 cost includes 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 which are 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 rejection episodes. Upon completion of induction phase, patient 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 of immunosuppresion regimen is dual regimens of steroid and calcineurin CNI (11). Some of the patients are also started on triple therahy as initial regimen before continuing with monotherapy of calcineurin inhibitor (12,13) Since CNI, steroid and antiproliferative immunosuppressant are the most commonly used immunosuppressant, hence we will discuss in depth on these 3 types of immunosuppresants in this section.
Hepatitis C infection & PBC
CyA + FTY720 to replace tacrolimus, sacrolimus and malononitrilamides
Low dose of steroid indefinitely
Rapid steroid wean (1 week)
Ensure on FK778
Leflunomide to replace MMF
Ensure on Fk778
Add statin, CyA or tacrolimus
Steroid (Wean over 12 weeks)
Basiliximab or Daclizumab
Low dose tacrolimus
Sorilimus or a malononitrilamide (FK778 or FK779)
Low dose tacrolimus
Sorilimus or a malononitrilamide
Figure 1: Proposed standard regimen of immunosuppression after liver transplant 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 liver transplant 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 which is the main cause of morbidity and mortality after liver transplantation, researches were carried to explore if the avoidance of CNIs usage can be employed. The related adverse effects and clinical evidences of these two drugs are shown in table 2.
O'Gray et al : Tacrolimus showed more benefits for adults with post liver transplant with respect to 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: Study 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)
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 used alongside with the CNIs in the maintenance immunosuppressant regimen in order to prevent rejection episodes-imu. However, due to the side effects exhibits 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 either receive a steroid or placebo on day 14 after liver transplant in combination with tacrolimus. (20). Consistent to this, a prospective randomised study by Vivarelli M et.al showed that the liver graft survival is dose related and the occurrence of reccurence disease was reduced if prednisolone dose is tapered slowly (21)
Azathioprine is one of the earliest antiproliferative immunosuppressant used in the treatment of liver transplant. Study 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 effect 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 has 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 exhibits nephrotoxicity and neurotoxicity (15). Various animal models was used to illustrate MMF efficacy and study showed that it reduces and slows down the onset of chronic rejection(24,25). Recent report 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 theraphy.
Nausea, vomiting, diarrhea
Connell WR : Study demonstrated 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 al: Study suggested that MMF monotheraphy improved 70% of the renal dysfunction cases at 6 months and 69.6% at 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 2 : 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 in combination with Tacrolimus which is a CNI and a steroid which dose will be tapered gradually and stop after 6 months. This combination is recommended instead of monotherapy regimen because studies had shown that the usage of MMF as monotherapy in liver transplantation will lead to undesirably high incidence of acute and severe chronic cellular rejection which required retransplantation and severe steroid-resistant rejection (30,31). MMF is the drug of choice instead of azathioprine because it is safer and it 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 the liver transplantation and episodes of liver rejection. Besides being more effective, MMF also has a better safety profile as it produces fewer side effects than azathioprine. However, there are no studies comparing these two antiproliferative immunosuppressant with placebo-control-group because it is not ethical to perform such studies when 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 acute rejection episodes was lower in MMF treated group in comparison to azathioprine group with incidence of 40.6% and 19.4% respectively with P value 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 is significantly lower in MMF treated patients (MMF: 19.4% versus AZA: 146.9%, P < .05). Similarly, leukopenia trend was also higher rate of in the MMF arm (MMF: 6.5% versus AZA: 18.8%, P = .12) but it was not significant. However, patient treated with MMF 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 signi¬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)
Wiesner R et al.
Cyclosporine and corticosteroid
Study showed that there was a significant different in the incidence of graft loss as MMF (1 g via IV BD, followed by 1.5 g BD orally) showed 38.5% and Azathioprine (1-2mg/kg/d IV followed by oral administration) showed 47.7% cases with with P value of less than 0.03. however there was no significant different in 1 year post transplantation patient and survival rates for MMF group (85.3%) and azathioprine group (85.4%) (36)
Table 3: Summarised studies on the effectiveness of azathioprine versus MMF
Eventhough the triple therapy of Tacrolimus, MMF and steroid was proven to be more effective in preventing acute rejection, however, many studies had demonstrated that CNIs will give rise to numerous of adverse effects to the patients (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 (ABOVE). Given that patient is a 64 year old male who is an elderly, the chances of him developing renal dysfunction is higher as age and gender is the risk factor of renal dysfunction. A study by Jungers P et al. demonstrated that annually, the incidence of renal failure in males doubled the females up to 75 years and incidence of renal failure in those who are 75 year old and above is three times as high (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 as 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. (logical approach!)In addition, MMF is also capable of reversing the nephrotoxicity secondary to CNI. Table 5 summarised some of the studies that showed the use of MMF monotherapy or combination with low dose of CNI is 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 Î¼mol/L in MMF group compared with 3·1 (14·3) Î¼mol/L CNI. 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)
MMF was introduced and tacrolimus dose was reduced by 30-50% with 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. After that, renal
function remained stable for 72 months. 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 : 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 statistically significant in preventing the acute rejection incidence, this will potentially result in the cut down of the cost on rejection-related treatment as there will be lower number or rejection episodes, decrease 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 azathiprine-based regimen.
Cost/year (US dollars)
Tacâˆ- + Aza + St.
Tacâˆ- + MMFâˆ- - St.
2500.00 / year
Table : Cost of immunosuppressive therapy in organ transplantation (44)