Our scenario is a 64 twelvemonth old male patient with a liver graft who requires an antiproliferative immunosuppressor. First, we will discourse the process in general with some grounds of survival rates statistic from other surveies. Then we will look into the complications that might happen after the liver graft and the best intervention options available for this peculiar patient.
1.0.2 Liver graft
Strazl and Calne established the cardinal techniques to successfully execute a liver graft surgery 15 old ages ago. Due to its added potency in bring arounding patients with chronic liver disease, liver graft has been quickly come oning over the last two decennaries. Presently, it is an constituted therapy for patients who suffer from irreversible end-stage liver failure. The process is normally considered in patients with chronic liver disease, malignance, congenital mistakes metamorphosis and fulminant liver failure ( 1 ) .
Surveies found that the one-year liver graft rate in the Europe is 5500 instances whereas in the United States there are 3925 instances, and the pediatric age group contributes 5 % of the overall graft rate in Europe ( 2,3 ) . A survey done by Jain A et Al. showed that the endurance rate was the lowest in patients who are more than 60 old ages old in comparing to the endurance rates for babies, kids and grownups with the age scope of below 2 twelvemonth old, 3 twelvemonth old to 18 twelvemonth old and 16 twelvemonth old to 60 twelvemonth old severally. The statistics for the 1, 5, 10, 15 and 18 old ages survival rates are summarised in the tabular array 1. This survey besides showed that the instances 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 malignant neoplastic diseases ( 11.6 % ) , cardiovascular ( 8.3 % ) and respiratory-related instances ( 7.0 % ) ( 4 ) .
Survival rates ( % )
5 old ages
10 old ages
14 old ages
15 old ages
18 old ages
& A ; lt ; 2 old ages
3 -18 old ages
16 – 60 old ages
& A ; gt ; 60 old ages
Table 1: Survival rate in station liver graft patients of different age group
1.0.3 Complication with liver graft
Regardless of the high post-transplant endurance rate, liver graft still poses a hazard to the patients. Complications of liver graft can be either immediate, long term or both. These complications normally occur as a consequence of preexistent disease, surgical processs and the response of the immune system against grafted organ.
Immediate complications in liver graft include proficient and medical complications, liver transplant disfunction, rejection and infections. Statisticss had revealed that proficient complications contribute an norm of 26 % of the overall immediate complications experienced by patients who undergo liver transplant. One of the most common proficient complications in liver graft is of arterial in beginning, peculiarly thrombosis of hepatic arteria which has the highest prevalence runing from 1.5 to 25 % . Others include bilious diseases and portal vena thrombosis, a really rare status with an overall prevalence of about 2 % to 3 % ( 5,6 ) . Medical complications include the side consequence of immunosuppressive drugs such as alterations nephritic map, haemodynamic related jobs, and affected neurological provinces ( 5,6 ) . Primary transplant disfunction is one of the most critical conditions that can take to decease or retrasplantation and the incidence of it happening is about 5-10 % ( 5,6 ) . Rejection is a major barrier in organ transplant. Immediate rejection can be either hyperacute or acute. Hyperacute rejection is antibody and complement mediated and it can happen within proceedingss to hours. On the other manus, acute rejection happens over a period of yearss to months. Another life endangering status is superadded infections. Statisticss showed that the figure of patients who have at least one morbific complication exceed half of liver transplant population and it contributes to more than 50 % of the rate of mortality in liver graft receiving systems ( 5,6 ) .
Long term complications
Patients with liver graft are prone to develop chronic rejection that will merely demo symptoms 6 months after the graft. Patients with chronic rejection will show with a loss of little bile canal and obliterative angiopathy on their biopsy consequences. Use of immunosuppressive agents may besides demo long term complications such as, chronic nephritic failure, osteopenia, diabetes mellitus ( a prevalence of 4 % to 20 % ) and atrial high blood pressure ( incidence rates runing from 50-70 % ) in the first few months after the graft. . Patient with a liver graft are besides prone to develop fleshiness with prevalence changing from 15 % to 40 % . In fact, there were besides instances of malignance being reported. The most common malignant neoplastic disease is the De novo malignance which shows an happening of 5 % to 15 % and the prevalence doubled in patient with malignant neoplastic disease. ( 5,6 )
1.0.4 Cost of graph failure and rejection
Immunosuppressive regimens after liver organ transplant can be really dearly-won as one battalion of antiproliferative immunosuppressor can be up to & A ; lb ; 200 ( 7 ) . If unequal immunosuppressive agents were given to the patient, this will take to rejection or transplant failure. A survey that was done by Martin et Al in 1998 showed that an norm of & A ; lb ; 16,561 is needed for one episode of rejection in liver graft. This sum covers the cost for diagnosing, intervention of rejection, complication related to rejection, outpatient medicines and place therapy. ( 8 )
2.0 Current immunosuppressive schemes and regimens
The immunosuppressant therapy is the basis of medical specialty for patients with liver graft. This regimen aims to keep the balance between the drug efficaciousness, drug toxicity and cost effectivity. The drug efficaciousness is assessed based on the happening of transplant rejection and survival rate. The current immunosuppressant regimen includes two stages: the initiation stage and the care stage. The Induction stage is a short term therapy and it commences during the perioperative period in order to queer off rejection episodes. Upon completion of initiation, patients will be introduced to the care stage government which is a long-run intervention. Maintenance therapy marks to minimise the use of immunosuppressor that is sufficient to forestall rejection while guaranting that the host immune system remains competent against infections and development of tumor ( 9,10 ) . The standard immunosuppressor government is shown in figure 1. In most of the organ transplant Centres, the combination of corticoids ( cortisol at initiation and so tapering steroid dosage ) , calcineurin inhibitor ( CNI ) and an antiproliferative immunosuppressor is used as the standard therapy. Another possible option is the double regimen of steroid and calcineurin CNI ( 11 ) . Some of the patients were besides started on ternary therapy as the initial class before go oning with a monotherapy of calcineurin inhibitor ( 12,13 ) . Since CNI, steroid and antiproliferative immunosuppressor are the most normally used immunosuppressor, we will discourse in deepness on these 3 types of immunosuppresants in this subdivision.
Figure 1: Proposed standard regimen of immunosuppression after liver organ transplant with the right box bespeaking the alteration that should be considered in specific fortunes. [ adapted from ( 14 ) ]
The debut of calcineurin inhibitors ( CNIs ) in 1970s had shed some visible radiation on patients ‘ lives. CNIs became the anchor immunosuppressor for station liver organ transplant immunosuppressor government and the most normally used CNIs are cyclosporine ( Csa ) and tacrolimus ( Tac ) . The debut of both Tacrolimus and Csa had improved the survival rate of the patient and transplant and reduces the incidence of station organ transplant ague rejection significantly ( 15 ) . However due to the broad array of side effects that were cause by the use of CNI such as, CNI induced chronic nephritic failure with arterial high blood pressure ( the chief cause of morbidity and mortality after liver organ transplant ) , researches were determined to research if turning away of CNIs use can be employed. The related inauspicious effects and clinical groundss of both drugs are shown in table 2.
High blood pressure
O’Gray et Al: Tacrolimus showed more benefits for grownups with station liver graft in footings of freedom from transplant loss and immunological failure. There was important difference between Csa and tacrolimus but the freedom from decease or retransplantation were non statistical significance ( comparative hazard 0.79 ; 95 % Confidence interval CI 0.62-1.02 ; P = .065 ) . ( 16 )
Ojo et Al. : Development of chronic nephritic failure in patients with nonrenal graft within 5 old ages post graft was up to 21 % and prevalence of nephritic disfunction after 15 old ages of liver transplantion was 18.1 % . Nephritic disfunction was straight associated with CNIs use. ( 17 )
Fisher et Al: demonstrated that 4 % of patients who survived the organ transplant after a twelvemonth developed chronic nephritic disfunction secondary to CNI use and 48 % of them advanced to stop phase nephritic failure and 44 died. ( Fisher RA, Ham JM, Marcos A, et Al: A t prospective randomized test of mycophenolate mofetil with neoral or tacrolimus after. ( 18 )
Wiesner RH. : Accumulative 5-year patient and transplant endurance rates for the patient on tacrolimus ( 79.0 % , 71.8 % ) were higher than cyclosporine ( 73.1 % , 66.4 % ) . Half-life endurance for tacrolimus-treated patients was longer ( 25.1+/-5.1 old ages versus 15.2+/-2.5 old ages ; P=0.049 ) and greater betterment of hepatitis C-positive patients who were tacrolimus was besides observed for ( Tac:78.9 % , Csa:60.5 % ; P=0.041 ) . ( 19 )
High blood pressure
Table 2: Summary of side effects and clinical results of CNIs
Corticosteroids are the most extensively used non-CNI drugs in liver graft. Steroids are normally combined with the CNIs for the care immunosuppressant regimen in order to forestall rejection episodes ( 14 ) . However, due to the side effects exhibited by corticoid such as hyperglycaemia, cushinoid syndrome, ulcers, myopathy, osteoporosis, fluid keeping, cataracts high blood pressure, mental position alterations, lipid abnormalcies, and impaired lesion healing, the turning away of corticosteroid use is favorable. A prospective randomized double blinded survey by Moench and co-workers demonstrated that the endurance rate was tantamount for both steroid and placebo group with 88 % and 85 % surviral severally. In this survey, the topics were randomized to have either a steroid or placebo on twenty-four hours 14 after liver graft in combination with tacrolimus. ( 20 ) . Consistent with this, a prospective randomised survey by Vivarelli M et.al showed that the liver transplant endurance is dose related and the frequence of reccurence diseases was reduced when the dosage of Pediapred was tapered down easy ( 21 )
Azathioprine is one of the earliest antiproliferative immunosuppressor used in the intervention of liver graft. Studies has shown that the use of Imuran is normally good tolerated if the dosage falls in the scope of 1·5 to 2·0 mg/kg/day and it is effectual in forestalling rejection episodes. However, azathioprine dose non hold important effects on established immune response ( 22 ) . Regardless of deficient randomized controlled tests that evaluate the clinical efficaciousness of Imuran in liver graft, Imuran remains as the conventional primary antiproliferative immunosuppression. However the use of Imuran was significantly reduced over clip chiefly due to the side effects posted by this drug and the debut of the newer, less toxic antiproliferative immunosuppression agents. ( 22,13 ) . The new antiproliferative immunosuppressor is mycophenolate compounds which come in two signifiers ; mycophenolate mofetil ( MMF ) and enteric-coated mycophenolate Na ( 23 ) . Mycophenolate compounds are really safe as their actions on the T cells and B cells do non impact the impacting bone marrow and parenchymal cells, hence it does non exhibit nephrotoxicity and neurotoxicity ( 15 ) . Assorted carnal theoretical accounts were used to exemplify MMF efficaciousness and surveies showed that it reduces and slows down the oncoming of chronic rejection ( 24,25 ) . Recent studies showed more than 50 % of the graft centres in the U.S have given their patients MMF within the first twelvemonth after liver organ transplant ( 26 ) . Table 3 summarises the side effects and the surveies done on these 2 drugs. Surveies on antiproliferative agents were performed as cyclosporine-a-based theraphy or tacrolimus-based therapy.
Nausea, purging, diarrhoea
Connell WRdemonstrated that 5 % of the patient showed mark of bone marrow toxicity, 3.8 % suffered from leucopenia, with 2 fatal instances due to sepsis and several of them developed pneumonia and mild mild upper respiratory infection merely. ( 27 )
Jain et Al. : A randomized cotrolled survey in 2 groups of primary grownup liver graft receivers that were on either tacrolimus and steroids or tacrolimus, steroids and MMF. The survey showed that lower episodes of acute cellular rejection we reported by patients who were on MMF, besides demoing betterment in patient and transplant endurance and nephritic map. Patients on MMF besides required lesser sum of care steroids and calcineurin inhibitors dose could be reduced in patients with important nephritic disfunction ( 28 )
Pulido LB et alsuggested that MMF monotherapy improved 70 % of the nephritic disfunction instances in 6 months and 69.6 % in 12 months with the decrease of serum creatinine degree from 1.63 mg/dL to 1.48 mg/dL whereas the is no alteration in the serum creatinine value in patients with normal nephritic map. The survey besides showed that MMF monotherapy was good tolerated and safe as it did non demo any increase the hazards of transplant rejection or loss. ( 29 )
Nausea, purging, diarrhoea
Bone marrow suppression
Table 3: Summary of side effects and clinical results of antiproliferative immunosuppressor
3.0 Recommendation of therapy
Immunosuppressant therapy should be tailored harmonizing to patient ‘s demands and conditions in order to cut down the rates of rejection, enhance transplant and patient endurance, and minimise the immunosuppressant-related toxicity. After reexamining the antiproliferative immunosuppressors available for current immunosuppression regimen, I would urge the use of MMF and Tacrolimus ( a CNI ) in combination with a steroid ( which will be tapered bit by bit and stopped after 6 months ) . This combination is recommended alternatively over MMF monotherapy regimen because surveies had shown that the use of MMF as a monotherapy in liver organ transplant will take to unwantedly high incidence of ague and terrible chronic cellular rejection, terrible steroid-resistant rejection and a subsequent demand for retransplantation ( 30,31 ) . MMF is the drug of pick alternatively of Imuran because it is safer and it is more effectual in forestalling transplant rejection in comparing to Azathioprine. The effectivity of MMF was interpreted from the rate of ‘patient and transplant endurance ‘ after liver organ transplant and episodes of liver rejection. Besides being more effectual, MMF has a better safety profile as it produces fewer side effects than Imuran. However, there are no surveies comparing both antiproliferative immunosuppressors with a placebo-control-group because of the ethical issues involved as we are cognizant that it is life endangering to order simply antiproliferative immunosuppressor or placebo to the patient with liver graft. Therefore, attendant usage of other immunosuppressor was manipulated to compare the effectivity of these two drugs and the surveies are summarised in table 6. In this instance, the CNI chosen was tacrolimus it safer and more efficacious than cyclosporine as the long term immunosuppressor after organ transplant. ( 32,33 )
Fischer L et Al.
Lymphocyte antibodies Corticosteroid cyclosporine A
The figure acute rejection episodes was lower in MMF treated group in comparing to azathioprine group with incidence of 40.6 % and 19.4 % severally and P value of 0.06. However patient endurance rate showed no important different between the two groups ( MMF: 90.3 % and AZA: 87.5 % ) . The happening of thrombocytopenia was significantly lower in MMFtreated patients ( MMF: 19.4 % versus AZA: 146.9 % , P & A ; lt ; 0.05 ) . Similarly, leukopeniatrend was besides lower in the MMF arm ( MMF: 6.5 % versus AZA: 18.8 % , P = 0.12 ) but it was non important. Patient treated with MMF in contrast exhibited GI side consequence more frequently than azathioprine treated patient, but they were ever mild. ( 34 )
Sterneck M et Al
Cyclosporine and steroid
There was a important decrease of acute rejection and transplant loss in MMF ( 1.5 g b.d. ) group in comparing 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 signii¬?cantly different in 1-year patient and transplant endurance rates for both group with MMF 88.8 % and 85.3 % versus AZA 87.1 % and 85.4 % , severally. ( 35 )
Table 4: Summarised surveies on the effectivity of azathioprine versus MMF
Although the ternary therapy of Tacrolimus, MMF and steroid was proven to be more effectual in forestalling acute rejection, many surveies had demonstrated that CNIs can give rise to legion inauspicious effects ( 37,38,39 ) . The most common CNI induced side effects experience by the patient is nephrotoxicity and this has been shown in many surveies in table 3. Given that patient is an aged 64 twelvemonth old gentleman, the opportunities of him developing nephritic disfunction is higher as age and gender are risk factors of nephritic disfunction. A survey by Jungers P et Al. demonstrated that yearly, the incidence of nephritic failure in males had doubled compared to females up to 75 old ages and, incidence of nephritic failure in those who are 75 twelvemonth old and above is three times higher ( 40 ) . Sing that this peculiar patient is at high hazard of developing nephritic disfunction after the beginning of CNI, MMF is hence recommended to the patient alternatively of Imuran. Furthermore, surveies had demonstrated that MMF was proven to be able to restrict the side consequence associated with CNI by leting the decrease in CNI dose sum or complete backdown of CNI ( 14 ) . In add-on, MMF is besides capable of change by reversaling the nephrotoxicity secondary to CNI which makes it a better pick of antiproliferative immunosuppresant. Table 5 summarised some of the surveies that showed the usage of MMF monotherapy or a combination with a low dosage of CNI is more favorable in commanding and change by reversaling CNI associated nephrotoxicity.
Schlitt et Al. ( 41 )
Replacement of CNI to MMF improves mean serum creatinine with the decrease of 44·4 ?mol/L in MMF group compared with 3·1 ( 14·3 ) ?mol/L in CNI group. Furthermore, systolic and diastolic blood force per unit area, and serum uric acid decreased significantly in the MMF group but non in the CNI group with average difference between groups of 10·8 millimeter Hg.
Jain et Al. ( 42 )
The debut of MMF and decrease of tacrolimus dosage by 30-50 % resulted in overall average serum creatinine decrease from 2.5 to 1.9 mg/dl at 6 months but increased to 2.2 mg/dl at 18 to 24 months. Renal map so remained stable for 72 months and 58 % of patients showed sustained betterment in nephritic map.
Jim & A ; eacute ; nez-P & A ; eacute ; rez M et Al. ( 43 )
CNI therapy was converted to monotherapy with MMF due to inauspicious events associated with CNIs and there was a progressive lessening in creatinine during the initial months. Compared with baseline degrees, the differences at 3 and 6 months of monotherapy were important ( P = 0.001 ) which remains so throughout the follow-up period. Nephritic map improved in 88 % of patients and normalized in 60 % of patients.
Table 5: Summarised surveies that show MMF monotherapy or combination with low dosage of CNI is favorable in commanding and change by reversaling CNI associated nephrotoxicity
Despite the fact that MMF-based regimens is more dearly-won than azathioprine-based regimens in liver graft receivers as shown in table 8, the MMF-based regimen is still desired due to the high quality of MMF over Imuran. In position of the fact that MMF is statistically important in forestalling the incidence of acute rejection, this will potentially ensue in the cut down of the cost on rejection-related intervention as there will be lower figure of rejection episodes, lessening in the length of hospitalization and finally decrease in transplant failure incidence. Therefore, the recommendation of utilizing MMF alternatively of Imuran is favorable as patients treated with MMF will be probably to hold lower intervention costs in comparing to patients who are on Imuran. MMF-based regimen is therefore more cost-efficient than azathioprine-based regimen. Therefore, taking into history patient ‘s status, the effectivity, safety profile and cost of MMF over Imuran in battling ague and chronic rejection episodes, MMF is the best pick of antiproliferative immunosuppressor in this peculiar patient.
Cost/year ( US dollars )
Tac-+ Aza + St.
Tac-+ MMF — St.
2500.00 / twelvemonth
Table 6: Cost of immunosuppressive therapy in organ organ transplant ( 44 )