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• W2000777898 abstract "INTRODUCTION Liver transplantation (LT) has emerged from an experimental therapy to a highly successful treatment for end-stage liver disease. Advances in immunosuppressive therapy have contributed significantly toward this achievement. The main goal of effective immunosuppression is the prevention of rejection with minimal complications. The early postoperative period after transplantation is critical and represents a time when the recipient is usually the most unstable, open to infections, and vulnerable to drug adverse effects. Thus, a careful balance is required between too much and too little immunosuppression. The introduction of calcineurin inhibitors (CNI) was an important landmark in transplantation; today they form the basis of most immunosuppressive regimens. During the past decade, agents that selectively target various cellular activation pathways have become increasingly available. This has not only resulted in lower rates of graft rejection but has provided transplant clinicians with much greater flexibility for devising and tailoring immunosuppression regimens that are well tolerated and meet specific patient requirements. In this review, we will discuss the current immunosuppressive agents and protocols most commonly used today for the prevention of liver and intestinal graft rejection and briefly mention novel strategies such as tolerance induction. HISTORY The first attempts at LT were reported in dogs in the mid 1950s (1). The organs were implanted without the use of immunosuppressive agents and were rapidly rejected. The first human orthotopic LT was attempted in 1963. The subsequent decade saw improvements in the surgical techniques and use of corticosteroids and azathioprine as the mainstays of therapy. However, immunosuppression was inadequate, with graft survival only around 30%. The introduction of cyclosporine (CSA) in the early 1980s (2) and subsequently tacrolimus (TRL) in the late 1980s (3) revolutionized the field of LT with 1-year graft and patient survival rates as high as 90%. Use (in adults) of mycophenolate mofetil (MMF) and sirolimus (SRL) was approved by the U.S Food and Drug Administration in 1995 and 1999, respectively. Subsequently, both were introduced into immunosuppression regimens in LT with the intention to decrease CNI side-effect frequency and as rescue agents. More recently, selective monoclonal antibodies (Abs) directed at the interleukin-2 receptor (IL-2R) are used for induction therapy to permit the safe and effective concomitant use of low-dose CNI. CORTICOSTEROIDS Corticosteroids are effective in both the prevention and treatment of graft rejection. They have several mechanisms of action including inhibition of IL-1 and IL-2 production, reduction in the proliferation of helper and suppressor T-cells, cytotoxic T-cells, and B-cells, suppression of Ab production and reduction in the migration and activity of neutrophils. Corticosteroids act through intracellular receptors expressed in almost every cell of the body. This likely explains the extensive list of potential side effects seen with these agents, most of which are dose related. The trend over the past 10 years has been to minimize and even eliminate the use of corticosteroids over the long term. The literature analyzing steroid withdrawal in pediatric LT is summarized in Table 1. The only randomized controlled trial was performed at UCLA (4). The patients (23 children, 44 adults) were randomized to receive either CSA-azathioprine with progressive steroid withdrawal (study group: n = 33) or a CSA-steroid (control group: n = 31) immunosuppressive regimen. Inclusion criteria were recipients of ABO identical or compatible grafts, more than 1 year after LT, with stable CSA blood levels, absence of rejection beyond 6 months after LT, and normal liver function tests at entry level. The protocol excluded patients who underwent LT for autoimmune hepatitis or with a previous history of graft loss or rejection. Steroid withdrawal was performed at a mean of 3.5 years post LT and resulted in a low incidence of secondary acute rejection episodes (6% in each group) with neither chronic rejection nor graft or patient loss. Several other centers have published uncontrolled series showing that steroid withdrawal can be achieved safely (5-11). The benefits of steroid withdrawal included improvement of growth and marked reduction of cushinoid features and hirsutism.TABLE 1: Studies on steroid withdrawal (SW) in pediatric liver transplant recipientsEarly steroid withdrawal (≤3 months postLT) was a feature of two prospective controlled studies in adults (12,13). The follow-up results revealed similar rates of rejection episodes and patient and graft survival. The benefits of early steroid withdrawal included significant reduction of the need for antihypertensive medications and a lower incidence of diabetes mellitus, infectious complications, and bone complications (12). In a prospective trial, use of MMF as a primary therapy in combination with either TRL or CSA allowed steroid withdrawal 14 days after LT with moderate incidence of acute rejection in both groups (46% and 42%, respectively, at 6 months follow-up postLT) (14). The combination of SRL with either CSA or TRL as a primary induction regimen in LT allowed safe steroid withdrawal 3 days postoperatively, with a significantly lower incidence of acute rejection compared with historic controls (15). Steroid withdrawal can be difficult in patients with underlying autoimmune liver disease. The experience with steroid withdrawal in one center indicates that underlying autoimmune disease (autoimmune hepatitis, inflammatory bowel disease) contributes to 43% of the reasons for failure of steroid withdrawal (16). However, 81% of patients with autoimmune hepatitis were successfully withdrawn from corticosteroids 6 months or more postLT (17). Patients receiving transplants for hepatotropic viral-induced cirrhosis are the subgroup who could gain most from steroid withdrawal (18,19). Corticosteroids still remain first line therapy for the treatment of acute rejection, given as a short course (3 days)of high-dose intravenous methyl prednisolone (10 mg/kg/day). Calcineurin Inhibitors CSA and TRL are referred to as CNIs because of the primary mechanism by which they inhibit T-cell responses (20). Both bind to a family of intracellular proteins known as immunophilins, cyclophilin and FK-binding protein, respectively. The immunophilin-drug complex competitively binds to and inhibits the phosphatase activity of calcineurin. Calcineurin inhibition indirectly blocks the transcription of cytokines, particularly IL-2, which drive the proliferative T-cell response. Both CSA and TRL (as well as SRL) are metabolized in the liver and small intestine by enzymes of the cytochrome P450 3A family (CYP3A), so their spectrum of drug interactions is quite similar. The most pronounced interactions are with the enzyme inducers rifampicin and phenytoin, resulting in reduced CNI levels, and with inhibitors such as many antifungal and antiviral protease inhibitor drugs and some calcium channel antagonists, all of which increase drug levels (Table 2). Interindividual pharmacogenetic differences in the genes encoding one of the CYP3A family members (CYP3A5) and the drug transporter P-glycoprotein (ABCB1) markedly influence the extent of absorption and metabolism of both CSA and particularly TRL. For example, the genetic variant CYP3A5*1 is metabolically active, present in 5% of whites, 25% to 30% of Asians, and approximately 75% of Afro-Caribbeans and is strongly associated with poor drug bioavailability and an adverse outcome after transplantation (21,22). A corresponding defective variant in ABCB1 (C3435T) is seemingly associated with a 50% reduced expression of Pgp in homozygotes, a higher drug bioavailability (23), and increased TRL blood levels in transplant patients expressing this variant (24). A recent summary of the effects of these variants on CNI immunosuppression has appeared (25).TABLE 2: Drug interactions for calcineurin inhibitors (CNI)CSA and TRL have similar side-effect profiles, which include dose-dependent nephrotoxicity, neurotoxicity, and hypertension because of their shared mechanism as CNI and despite their structural differences. Most adverse effects are reversible after early dose reduction or discontinuation of the drug (26,27). Cosmetic adverse effects such as hypertrichosis and gingival hyperplasia have not been associated with TRL, which is an advantage that may improve drug compliance, particularly in older children and adolescents. TRL is associated with less hyperlipidemia and a lower adverse cardiovascular risk profile than CSA (28,29) but with slightly more de novo diabetes and gastrointestinal symptoms (30). Because of its more potent immunosuppressive effect, TRL appears to have a higher incidence of posttransplant lymphoproliferative disease (PTLD) (31). Hypertrophic cardiomyopathy has been reported with prolonged use of TRL at unusually high levels (32). CNIs continue to form the backbone of most induction regimens. Data from the Studies of Pediatric Liver Transplantation (SPLIT) 2002 annual report (33) indicates that TRL use has increased from 29.3% in 1996 to 67.6% in the year 2000, with steady decline in the use of CSA. Large, multicenter U.S. (34) and European trials (35) comparing TRL and CSA induction regimens have shown similar 1-year patient and graft survival. The TRL group in both studies had a significantly reduced incidence of acute rejection as well as steroid-resistant rejection. TRL is superior to CSA for the treatment of rejection episodes: bouts of acute rejection, even steroid-resistant episodes, may resolve when patients are switched from CSA to TRL therapy (36,37). King's College Pediatric Liver Unit reported their experience with CNIs in 164 children, 131 of whom received primary CSA and 33 primary TRL-based immunosuppression (38). Of the 79 (60%) children on primary CSA who were converted to TRL at a median of 11 days after LT, this occurred within 1 month in 64 (81%). The incidence of acute rejection was significantly higher in the CSA-based immunosuppression group compared with TRL (67% vs. 30%, P < 0.001), and other centers report that more than half of patients with chronic rejection respond when converted from CSA to TRL (39). Cyclosporine Pharmacokinetics CSA is absorbed mainly from the small intestine (40) and is metabolized there and in the liver by the cytochrome P4503A (CYP3A) enzyme system. The majority of metabolites are excreted in bile (41). The guidelines for dosing and monitoring CSA are based mainly on the pharmacokinetics of the drug in adult patients. However, there are unique features to consider regarding pharmacokinetics of CSA in children. First, the bioavailability of CSA correlates with age, being lower in younger patients (42). Second, children typically have a higher rate of CSA metabolism than adults, which appears to be inversely related to age (42). Absorption and bioavailability may be further affected by concomitant disease (e.g., cystic fibrosis), where intestinal absorption is dependent on pancreatic enzyme supplementation (43-46) and by the type of biliary anastomosis (e.g., Roux-en-Y biliary anastomosis for biliary atresia). Neoral, the microemulsion form of CSA, has replaced the original formulation Sandimmune because of its greater and more consistent bioavailability. Its absorption is both more rapid and more extensive as judged by an increased area under the plasma concentration time curve (AUC) (47). In particular, younger children and children with Roux-en-Y biliary anastomosis or cholestasis showed more consistent drug absorption with Neoral (48-50). Studies using Neoral have shown a reduced incidence of rejection as compared with Sandimmune in liver recipients, with no significant difference in toxicity (51-53). Dosing and Monitoring The recommended starting dose of Neoral (5 mg/kg/dose twice daily) should be administered within the first 12 hours of abdominal closure. Where poor absorption or inadequate trough concentrations persist, intravenous CSA is administered at a dose of 2 mg/kg per day in two divided doses by continuous infusion over 2 to 6 hours. Dose adjustment is required to keep trough concentrations within a recommended target range (Table 3).TABLE 3: Trough concentrations of calcineurin inhibitors after liver transplantationCSA monitoring continues to be a point of discussion. Despite pharmacokinetic improvement, trough levels (C0) were weak or even poor predictors of rejection episodes or outcome of graft recipients (54). In recent years, pharmacokinetic studies in adult and pediatric LT recipients have shown that the CSA drug concentration in blood drawn 2 hours postdose (C2) is superior to the traditional determination of CSA trough concentrations (C0) taken as an estimate of the subsequent 12 hour CSA exposure (47,55,56). Neoral absorption during the first 4 hours postdose (AUC 0-4 hours) represents the period of greatest variability among patients. C0 does not correlate with AUC 0 to 4 hours, and C2 is the best single time point predictor in all types of pediatric solid organ transplantation (57). Although there are no data showing a benefit of C2 monitoring for patient and graft survival in the long term, its value for patient management and lowering the risk of renal toxicity and acute graft rejection is evident (58-60). Neoral C2 target levels need to be determined for specific age groups, transplant type, and for distinct intervals posttransplant. Tacrolimus Pharmacokinetics TRL is a highly hydrophobic drug formulated to be absorbed independently from bile salts. After absorption, 90% is associated with erythrocytes and white cells, and the remaining low concentrations of drug are bound extensively to plasma proteins (61). Similar to CSA, TRL is metabolized by the CYP3A enzyme family in the liver and intestine and is excreted in bile (62), showing large inter- and intra-individual differences in pharmacokinetic properties. The elimination half-life of TRL in children is 50% of that in adults, and clearance is correspondingly two to four times faster (63-66). Therefore, children require higher doses to achieve similar TRL concentrations. Dosing and Monitoring The recommended starting dose of 0.15 mg/kg/dose is administered within the first 12 hours after abdominal closure. Subsequent doses are reduced to 0.05 to 0.1 mg/kg/dose twice daily orally. Dose adjustments are required to maintain trough concentrations within a recommended target range (Table 3). For routine TRL drug level monitoring, the trough level is widely accepted, despite showing only a weak correlation with rejection or graft outcome. Although reports describe a closer correlation of the C2 and particularly C4 or C5 concentrations (66,67) with AUC, the manufacturer has suggested that any benefit over C0 is insufficient to warrant routine use of nontrough samples, but this needs independent validation. Mycophenolate Mofetil Pharmacodynamics MMF is almost completely absorbed after oral administration and rapidly hydrolyzed into its active metabolite, mycophenolic acid (MPA), by tissue esterases (68). MPA is a selective inhibitor of the enzyme inosine monophosphate dehydrogenase (IMPDH), which is a prerequisite for the de novo pathway of purine synthesis, on which B and T cells are dependent for DNA replication and cellular activation (69-71). Inhibition of IMPDH and the de novo pathway results in the depletion of guanosine nucleotides and arrested replication because lymphocytes are unable to use alternative pathway for nucleotide production (72,73). In contrast with lymphocytes, neutrophils can use both de novo and alternative salvage pathways, and therefore they are less likely to be affected by MMF. Pharmacokinetics MPA undergoes enterohepatic circulation with a secondary peak 6 to 12 hours after oral administration (74). However, this late peak was absent from full AUC profiles obtained in pediatric LT recipients (75). It has been proposed that liver graft recipients without a gall bladder may lack this bolus of biliary MPA glucuronide (MPAG) from which this second peak is derived. MPA is extensively bound to serum albumin and is glucuronated in the liver and excreted by the kidney. The terminal half-life is nearly 18 hours in healthy subjects but shorter in transplant recipients. Renal impairment and decreased serum albumin lead to an increase in MPAG, the free fraction of MPA, and free MPA-AUC values (74,76,77). Dosing and Monitoring In adults, the recommended initial dosage is 2 g per day in two divided doses orally, increasing to 1.5 g twice daily as required. A recent data from our center suggested that an MMF dose of approximately 15 mg/kg/dose given twice a day could be the most suitable dose for pediatric LT recipients (75), but this needs confirming in a larger cohort of patients. The increasing evidence of good pharmacokinetic and pharmacodynamic correlations with MMF treatment (78-81) and the large interindividual variations in MPA pharmacokinetic parameters (75,82) reinforce the need for therapeutic drug monitoring and individualized dosing. Studies of adult renal transplant recipients have shown relationship between MPA AUC 0 to 12 hours and allograft rejection: as AUC0-12 MPA increased, the probability of acute rejection decreased (78). MPA C0 correlated closely with AUC in a small cohort of pediatric LT recipients (75) and was related to efficacy and side effects in liver graft recipients (76). A therapeutic range of predose MPA plasma levels of 1 to 3.5 mg/L (by immunoassay) has been suggested in liver allograft recipients given adjunctive MMF (76). The frequency of monitoring will clearly depend on the clinical condition of the patient, but a policy of decreasing testing with time after transplantation and with increasing clinical stability seems appropriate. Clinical Efficacy A number of studies in adult LT recipients have included MMF in triple drug induction combinations as an alternative to azathioprine, with significant reduction of the rates of allograft rejection (83,84). Prospective controlled trials in the use of MMF as adjunctive therapy to primary immunosuppressive regimens in pediatric LT are ongoing. MMF was found to be an effective alternative immunosuppressive agent in patients with chronic rejection, refractory rejection, or severe CNI toxicity (22,85-91). MMF also appears to facilitate the use of reduced dose CNI in LT recipients, without increasing the risk of rejection, resulting in a decreased incidence of CNI-related nephro- and neurotoxicity (92). A further advantage of MMF is to facilitate early steroid withdrawal (14,92,93). Adverse Effects and Drug Interactions The main side effects of MMF are dose dependent gastrointestinal (30%) and bone marrow suppression (3%), which usually resolve after dose reduction (75,76,94). MMF also has been associated with a slightly increased frequency of opportunistic infection and lymphoproliferative disease, as occur with any immunosuppressive regimen. Acyclovir and ganciclovir increase MPA efficacy, whereas cholestyramine may interfere with the enterohepatic circulation of MPA, and therefore reducing its concentration in the circulation. Oral antibiotics may also decrease circulating MPA levels as may the administration of antacids that reduce intestinal absorption of MMF (94). Comedication with CSA increased MMF dosage requirements compared with children on TRL therapy (75,82), but high TRL concentrations may also decrease circulating MPA levels. To avoid potential toxicity or loss of efficacy, MPA monitoring is required where dose changes or interconversion of CSA and TRL are being undertaken and where drug interactions are suspected. Sirolimus Pharmacodynamics SRL (rapamycin) is a macrolide antibiotic isolated from the fungus Streptomyces hygroscopicus, with potent immunosuppressive properties (95). Despite having structural similarities to TRL, as well as the same intracellular binding protein (FKBP12), SRL acts differently from CNIs: its mechanism is to block T-cell activation by way of IL-2R postreceptor signal transduction, whereas CNIs interfere with IL-2 gene transcription. This is achieved by inhibition of the mammalian target of rapamycin (mTOR) by the SRL-FKBP12 complex, resulting in the inhibition of tyrosine kinase, which is essential for cytokine-driven T-cell activation and proliferation (95). There is experimental data suggesting that SRL has additional antineoplastic (96) and antifibrotic activity (97). Pharmacokinetics SRL is a highly lipophilic drug that is absorbed rapidly from the gastrointestinal tract (95). It is metabolized by the CYP3A enzyme family and therefore has a drug interaction profile similar to the CNIs (Table 2). Its half-life is long (40-86 hours) and shows intra- and interindividual variation, leading to a poor correlation of the dose to either C0 or AUC (95,98). SRL levels are known to significantly increase during simultaneous administration of CSA (but not TRL), and dosage 4 hours after CSA is recommended (99). SRL allows 50% reduction in CSA exposure (100). Pharmacokinetic studies showed excellent correlation between C0 and AUC (98,101,102) and that whole blood peak concentrations are reached within 2 to 3 hours after administration of a single oral dose (103-105). C0 values were correlated with clinical outcomes, with C0 greater than 15 μg/L associated with increased incidence of adverse effects (106), and values of 6 to 12 μg/L reported to yield low rates of graft rejection and toxicity (107). Dosing and Monitoring Optimal dosing for SRL is still under investigation. A single daily dose up to 15 mg/m2 has been well tolerated (105). In adults, it is often given as one time oral loading dose of 6 to 9 mg, followed by once daily dosing of 2 to 5 mg. Daily monitoring of SRL is not necessary because of the long half-life of the drug (108). To allow proper tissue saturation, the first reliable SRL measurements will not be obtained until day 4 of therapy. Thereafter, monitoring C0 twice weekly for the first month and weekly for the next month is recommended, targeting a 5 to 15 μg/L range. After the second month, drug levels should be measured regularly in children to accommodate growth and as warranted clinically by changes in comedication with drugs affecting CYP3A enzymes, changes in CSA dosage, deterioration in hepatic function, or suspicion of noncompliance, gastrointestinal disturbances, or exaggerated toxicity (108). Clinical Efficacy The efficacy of SRL in solid organ transplantation was shown initially in the renal transplant population. Randomized, prospective studies in renal graft recipients revealed that SRL-based immunosuppression is comparable with CSA-based immunosuppression in preventing acute rejection and maintaining excellent patient and graft survival (109,110). Small, uncontrolled studies in LT recipients have shown SRL to be an effective agent when combined with a CNI (Table 4). These series suggest that putative synergistic effects of SRL permit LT with low rates of acute rejection using CNI at low doses below the threshold for overt toxicity (107,111-115). It facilitated early steroid withdrawal while maintaining low rates of acute rejection when used in conjunction with CNI (107,111,112,114). Additional advantages of SRL were demonstrated during rescue treatment after chronic rejection and as an effective replacement agent in CNI-based immunosuppressive regimens in stable LT patients after their withdrawal to counter CNI-induced neuro- and nephrotoxicity (115-118). An attempt to use SRL as a single primary immunosuppressive agent in a small series of LT recipients resulted in a high rate of acute rejection (80%) (111), probably indicating that SRL should be used in a multidrug regimen.TABLE 4: Studies on use of interleukin-2 receptor antibodies in a primary immunosuppressive regimen in pediatric liver transplant recipients.The antineoplastic activity of SRL (109), achieved by inhibiting angiogenesis in malignant tissue through reduction of vascular endothelial growth factor secretion, may provide a specific indication for using SRL after transplantation for hepatocellular carcinoma (119,120). Adverse Effects Perhaps the greatest potential benefit of SRL in LT recipients is its lack of nephrotoxicity and neurotoxicity. The most frequent dose-related adverse effects of SRL include hyperlipidemia, thrombocytopenia, and leukopenia, but also observed are mouth ulcers, skin rash/acne, joint pains, and peripheral swelling/edema, particularly of the lungs (107,115,121). Information involving the long-term safety and efficacy of SRL in liver allograft is not available, and the Food and Drug Administration has not approved SRL for use in LT, although several trials have been reported (Table 5). One large multicenter trial to evaluate preemptive SRL therapy in LT recipients was halted as a result of an increased incidence of hepatic artery thrombosis (5.5%) (122). In contrast, other studies have shown no higher incidence of hepatic artery thrombosis (114,123-125) and a possible benefit of SRL in the prevention of coronary artery restenosis (126). Further large, controlled studies are required to determine whether SRL has important thrombotic effects. There is anecdotal information but no direct evidence that SRL negatively impacts wound healing in transplant recipients (109,111,125). On the basis of these limited data, higher oral doses and blood levels (C0 > 20 μg/L) should be avoided because they may be associated with a higher incidence of wound complications, and the drug does have antifibrotic effects that could underlie impaired wound healing. Further studies are required on the influence of SRL on wound complications after LT.TABLE 5: Studies on use of sirolimus and low dose calcineurin inhibitor in a primary immunosuppressive regimen in adult liver transplant recipientsInterleukin-2 Receptor Antibodies T cells involved in acute rejection are characterized by the expression of activation markers such as the IL-2 R. The high-affinity IL-2R complex consists of at least three subunits: IL-2R alpha (CD25), IL-2R beta (CD122), and IL-2R gamma (CD132) (127). Only IL-2R alpha is expressed on the surface of activated T cells, whereas the other subunits are expressed on resting T cells (128). Therefore, anti-IL-2 R target therapy appears to be a promising chance for specific immunosuppression. Initial results with murine IL-2 R Abs appeared promising, but a significant limitation was the short half-life and the formation of antimurine Abs (129), rendering the drugs ineffective within 2 weeks posttransplant. To circumvent these problems, chimeric (basiliximab [BAS, Simulect, Novartis, Basel, Switzerland]) and humanized (daclizumab [DAC, Zenapax, Roche, Basel, Switzerland]) forms of these Abs were developed. These are less immunogenic and have much longer half-lives. Pharmacodynamics, Pharmacokinetics, and Dosing DAC is a molecularly engineered human immunoglobulin G1 monoclonal Ab that binds to, but does not activate, the high-affinity IL-2 R and has a half life of approximately 11 days in renal transplant patients (130). BAS is a chimeric Ab that contains less than 10% murine sequences and has a half-life of approximately 6.5 days in renal transplant recipients (131). Pharmacokinetic studies in adult renal transplant recipients, based on dual dosage regimen for BAS (20 mg on days 0 and 4) and five doses regimen for DAC (1 mg/kg on day 0, then at 2, 4, 6, and 8 weeks postoperatively), have demonstrated receptor suppression for approximately 3 to 4 weeks for BAS and up to 10 weeks for DAC (132,133). The optimal length of receptor suppression and whether it is significant beyond 4 weeks is unknown. The half-life of BAS was lower in LT than renal transplant recipients (124), and clearance through drained ascites fluid or by extensive postoperative blood loss in LT patients was suggested as the cause (134,135). BAS administered as dual dosage regimen produced IL-2 R suppression of 23 ± 5 days (134) and up to 38 ± 16 days in another study (132) and a half-life of 4.1 ± 2.1 days (134). In children, BAS is given as a two-dose regimen of 10 mg intravenously (body weight <35 kg) or 20 mg (body weight >35 kg) on day 0 (immediately pre or within 6 hours postoperatively) and day 4. For DAC, a variety of different dosing regimens have been evaluated, varying from a single dose of 2 mg/kg (136) to dual and triple dosage regimens (137). It is now accepted that a dual regimen of 1 mg/kg on day 0 and 4 after surgery will provide receptor saturation for up to 21 days. It has been suggested that dose adjustments or further dosing is considered for patients with massive ascetic fluid drainage or when no or only a low level of CNI drugs are being used (137). Studies with BAS have identified that 0.2 μg/mL is the minimum effective serum concentration required to saturate IL-2 R epitopes (138). The minimum concentration of DAC required to inhibit IL-2 proliferation and suppress CD3 cells count is 1 μg/mL (135), with maximum effect at trough levels of 5 to 10 μg/mL. Clinical Efficacy There are ongoing trials with both Abs in adult LT recipients. The possibility of induction therapy with DAC, MMF, and corticosteroids, but without CNI, was explored in a pilot study in LT (139). The study was halted after the first seven patients developed acute rejection. In the same study, 25 patients received DAC, MMF, and corticosteroids with delayed introduction of low dose CNI, on average 7 days postoperatively. The most important factor influencing acute rejection appeared to be the delay in instituting CNI, with 91% of patients receiving CNI after posttransplant day 8 experiencing acute rejection versus 29% of those commenced before d" @default.
• W2000777898 created "2016-06-24" @default.
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• W2000777898 date "2005-08-01" @default.
• W2000777898 modified "2023-10-18" @default.
• W2000777898 title "Immunosuppression in Pediatric Liver and Intestinal Transplantation: A Closer Look at the Arsenal" @default.
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