Our scenario is 64 twelvemonth old male patient with a liver graft who requires an antiproliferative immunosuppressor. First, we will discourse a liver graft 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 what are the best intervention options available for this peculiar patient.
1.0.2 Liver graft
Strazl and Calne established the cardinal techniques to execute liver graft successfully 15 old ages ago.A Due to its possible in bring arounding patients with chronic liver disease, liver graft has been come oning quickly over the last two decennaries. Presently, Liver graft is an constituted therapy for patients who suffer from irreversible end-stage liver failure. Liver transplant process is normally considered in patient 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 pediatric instances contribute 5 % of the overall graft rate in the 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 related instances ( 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
& lt ; 2 old ages
3 -18 old ages
16 – 60 old ages
& 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 posts complications to the patients. Complications in liver graft can be either immediate or long term or both. These complications normally occur due to preexistent disease, surgical processs and the response of the immune system against grafted organ.
Immediate complications in liver graft include proficient complication, medical complication, liver transplant disfunction, rejection and infections. Statistic showed 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 arterial complications, peculiarly thrombosis of hepatic arteria which has the highest prevalence runing from 1.5 to 25 % . Other proficient complications include portal vena thrombosis which is really rare with an overall prevalence of about 2 % to 3 % and bilious complications ( 5,6 ) . Medical complications include the side consequence of immunosuppressive drugs such as heamodynamic complications, alterations renal map and neurological province ( 5,6 ) . Primary transplant disfunction is one of the most critical immediate complications occurs that will 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 occurs witin proceedingss to hours. Acute rejection nevertheless happens over a period of yearss to months. Another life endangering complication is the infections. Statistic showed that the figure 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 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 organ transplant. Patients with chronic rejection will demo consequences which show the loss of little bile canal and obliterative angiopathy on their biopsy consequences. Similar immediate complications, some long term complications are besides resulted from the use of immunosuppressant agents such as chronic nephritic failure, osteopenia, diabetes mellitus that showed 4 % to 20 % of the patients develop diabetes mellitus subsequent to transfer and atrial high blood pressure with the prevalence runing from 50-70 % in the first few months after the graft. . Patent with liver graft will besides prone to be corpulent with the prevalence varies from 15 % to 40 % . There were besides instances of maglinancy reported by patient with liver graft. The most common malignance is the De novo malignance which show happening between 5 % to 15 % in patients and the prevalence two-base hit in patient with malignant neoplastic disease. ( 5,6 )
1.0.4 Cost of graph failure and rejection
After organ transplant, patient will be on the Immunosuppressive regimen which is really dearly-won as one battalion of antiproliferative immunosuppressor can be up to ?200 ( 7 ) . If unequal immunosuppressive agents were given to the patient, it will take to rejection or transplant failure. A survey that was done by Martin et Al in 1998 showed that an norm of ?16,561 is needed for one episode of rejection in liver graft. This cost includes 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 which are 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 rejection episodes. Upon completion of initiation stage, patient 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 of immunosuppresion regimen is double regimens of steroid and calcineurin CNI ( 11 ) . Some of the patients are besides started on three-base hit therahy as initial regimen before go oning with monotherapy of calcineurin inhibitor ( 12,13 ) Since CNI, steroid and antiproliferative immunosuppressor are the most normally used immunosuppressor, hence we will discourse in deepness on these 3 types of immunosuppresants in this subdivision.
Hepatitis C infection & A ; PBC
CyA + FTY720 to replace tacrolimus, sacrolimus and malononitrilamides
Low dosage of steroid indefinitely
Rapid steroid wean ( 1 hebdomad )
Ensure on FK778
Add lipid-lowering medicine
Leflunomide to replace MMF
Ensure on Fk778
Add lipid-lowering medicine, CyA or tacrolimus
Steroid ( Wean over 12 hebdomads )
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 graft 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 liver graft 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 which is the chief cause of morbidity and mortality after liver organ transplant, researches were carried to research if the turning away of CNIs use can be employed. The related inauspicious effects and clinical groundss of these two drugs are shown in table 2.
High blood pressure
O’Gray et Al: Tacrolimus showed more benefits for grownups with station liver graft with regard to 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: Study 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 used alongside with the CNIs in the care immunosuppressant regimen in order to forestall rejection episodes-imu. However, due to the side effects exhibits 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 either have a steroid or placebo on twenty-four hours 14 after liver graft in combination with tacrolimus. ( 20 ) . Consistent to this, a prospective randomised survey by Vivarelli M et.al showed that the liver transplant endurance is dose related and the happening of reccurence disease was reduced if Pediapred dosage is tapered easy ( 21 )
Azathioprine is one of the earliest antiproliferative immunosuppressor used in the intervention of liver graft. Study has shown that the use of Imuran is normally good tolerated if the dosage falls in the scope of 1A·5 to 2A·0 mg/kg/day and it is effectual in forestalling rejection episodes. However, azathioprine dose non hold important consequence on established immune response ( 22 ) . Regardless of deficient randomizedA controlled tests that evaluate the clinical efficaciousness of azathioprineA in liver graft, Imuran remains as the conventional primary antiproliferative immunosuppression. However the use of Imuran has 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 exhibits nephrotoxicity and neurotoxicity ( 15 ) . Assorted carnal theoretical accounts was used to exemplify MMF efficaciousness and survey showed that it reduces and slows down the oncoming of chronic rejection ( 24,25 ) . Recent study 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 theraphy.
Nausea, purging, diarrhoea
Connell WR: Study demonstrated 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 Al: Study suggested that MMF monotheraphy improved 70 % of the nephritic disfunction instances at 6 months and 69.6 % at 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 thatA MMFA 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 2: 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 in combination with Tacrolimus which is a CNI and a steroid which dosage will be tapered bit by bit and halt after 6 months. This combination is recommended alternatively of monotherapy regimen because surveies had shown that the use of MMF as monotherapy in liver organ transplant will take to unwantedly high incidence of ague and terrible chronic cellular rejection which required retransplantation and terrible steroid-resistant rejection ( 30,31 ) . MMF is the drug of pick alternatively of Imuran because it is safer and it 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 the liver organ transplant and episodes of liver rejection. Besides being more effectual, MMF besides has a better safety profile as it produces fewer side effects than Imuran. However, there are no surveies comparing these two antiproliferative immunosuppressant with placebo-control-group because it is non ethical to execute such surveies when 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.
LymphocyteA antibodies Corticosteroid cyclosporine A
The acute rejection episodes was lower in MMF treated group in comparing to azathioprine group with incidence of 40.6 % and 19.4 % severally with P value 0.06. However patient endurance rate showed no important different between the two groups ( MMF: 90.3 % and AZA: 87.5 % ) . The happening of thrombopeniaA is significantly lower in MMF treated patients ( MMF: 19.4 % versusA AZA: 146.9 % , PA & lt ; .05 ) . Similarly, leukopenia tendency was besides higher rate ofA A in theA MMFA arm ( MMF: 6.5 % versusA AZA: 18.8 % , PA = .12 ) but it was non important. However, patient treated with MMF exhibited Gastrointestinal 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 )
Wiesner R et Al.
Cyclosporine and corticosteroid
Survey showed that there was a important different in the incidence of transplant 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 unwritten disposal ) showed 47.7 % instances with with P value of less than 0.03. nevertheless there was no important different in 1 twelvemonth station organ transplant patient and endurance rates for MMF group ( 85.3 % ) and azathioprine group ( 85.4 % ) ( 36 )
Table 3: Summarised surveies on the effectivity of azathioprine versus MMF
Eventhough the ternary therapy of Tacrolimus, MMF and steroid was proven to be more effectual in forestalling acute rejection, nevertheless, many surveies had demonstrated that CNIs will give rise to legion of inauspicious 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 surveies in tabular array ( ABOVE ) . Given that patient is a 64 twelvemonth old male who is an aged, the opportunities of him developing nephritic disfunction is higher as age and gender is the hazard factor of nephritic disfunction. A survey by Jungers P et Al. demonstrated that yearly, the incidence of nephritic failure in males doubled the females up to 75 old ages and incidence of nephritic failure in those who are 75 twelvemonth old and above is three times every bit high ( 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 as 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. ( logical attack! ) In add-on, MMF is besides capable of change by reversaling the nephrotoxicity secondary to CNI. Table 5 summarised some of the surveies that showed the usage of MMF monotherapy or combination with low dosage of CNI is 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 44A·4 I?mol/L in MMF group compared with 3A·1 ( 14A·3 ) I?mol/L CNI. 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 10A·8 mmA Hg.
Jain et Al. ( 42 )
MMF was introduced and tacrolimus dosage was reduced by 30-50 % with 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. After that, nephritic
map remained stable for 72 months. 58 % of patients showed sustained betterment in nephritic map.
Jimenez-Perez 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: 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 statistically important in forestalling the acute rejection incidence, this will potentially ensue in the cut down of the cost on rejection-related intervention as there will be lower figure or rejection episodes, diminish 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 azathiprine-based regimen.
Cost/year ( US dollars )
Taca?- + Aza + St.
Taca?- + MMFa?- – St.
2500.00 / twelvemonth
Table: Cost of immunosuppressive therapy in organ organ transplant ( 44 )