Safety and feasibility of duct-to-duct biliary anastomosis in pediatric liver transplantation: A single-center retrospective study

Background: Roux-en-Y hepaticojejunostomy(HJ) is the standard-of-care for biliary reconstruction in pediatric liver transplantation(LT), especially in left sided grafts. This study aimed to investigate the learning curve and the risk of biliary complication of duct-to-duct biliary anastomosis(DDA) in pediatric LT using left sided grafts. Method: This was a retrospective study from a surgical unit of a university-affiliated center. From 2017-2020, DDA was performed in pediatric LT with a high hilar dissection and patch anastomosis technique under a prospective protocol.(Figure 1) The exclusion criteria were: 1) disease mandated HJ, 2) widely separated graft bile ducts that ductoplasty was infeasible, 3) native biliary anatomical factors that rendered a patch infeasible. Size discrepancy was not a contraindication. The primary endpoint was the risk of biliary complication at 1-year after LT. Results: During study period, 137 pediatric recipients fulfilled inclusion and were considered eligible for DDA, 110 (80.3%) patients had DDA. The pre-transplant characteristics were listed in table 1. The first 40 patients belonged to learning curve period and after that, more patients were eligible for DDA (7.2% vs. 15.1%, P<0.001). The overall risk of biliary complication at 1-year was 2.9% (4/137) and it was higher in the learning phase (9.1% vs 1.3%, P=0.045). Of the 4 biliary complications: 1 had bile leakage and stricture and required endoscopic stenting; 3 had biliary stricture with 2 required conversion to HJ and 1 had endoscopic stenting. All 4 patients have normal graft function at time of analysis. There was only one hospital mortality (1/137, 0.7%) and was due to post-operative bleeding and was unrelated to biliary complication. Graft survival rates at 1-and 3-year after DDA were 98.2% and 96.8% respectively. Conclusion: DDA was safe and feasible with excellent perioperative and long-term outcomes and should be considered the primary choice for biliary reconstruction in eligible pediatric transplant patients.

The chance of biliary complication after living donor liver transplantation (LDLT) is considerable. The objective of this study was to investigate the impact of biliary reconstruction method on post-LDLT biliary complications. Data sources are from PubMed and Web of Science. A systematic search was conducted using the search term '[biliary complications] OR [biliary complication] OR [biliary stricture] OR [bile leak] AND [living donor liver transplantation]'. Cross-referencing was allowed so as to encompass more potentially relevant studies. All English papers on adult LDLT published between 1990 and 2014 were considered for review. Papers focusing on biliary reconstruction method in relation to post-LDLT biliary complications were included. The meta-analysis recruited six retrospective studies but no randomized trial or prospective study. The six studies covered 1286 patients with 260 cases (20.2%) of biliary anastomotic stricture (BAS) and 118 cases (9.2%) of biliary leakage (BL). For biliary reconstruction, 365 patients (28.4%) underwent hepaticojejunostomy (HJ) and 909 (70.7%) underwent duct-to-duct anastomosis (DDA), while 12 (0.9%) underwent both and were thus excluded from the analysis. A lower rate of BAS was found in patients with HJ compared with patients with DDA (Mantel-Haenszel odds ratio 0.448, 95% confidence interval 0.311-0.643; P = 0.000). Rates of BL were similar in the two groups (Mantel-Haenszel odds ratio 1.27, 95% confidence interval 0.821-1.966; P = 0.283). In the comparison of HJ and DDA in adult LDLT, the latter was found to be associated with a bigger chance of BAS but not BL.

The most common types of biliary reconstruction in pediatric liver transplantation are end-to-end choledochocholedocostomy (CC) and choledochojejunostomy (CJ). Choledochoduodenostomy (CD) is seldom used, and consequently, there are very few reports in the literature about the outcomes of CD reconstruction in pediatric liver transplants. We hypothesized that CD is a safe alternative for pediatric liver transplantation. Between January 2017 and February 2024, 186 consecutive primary liver transplants in children (<21y) were performed at Stanford Medicine Children's Health. Seventy-three patients underwent CC, 55 underwent CJ, and 41 underwent CD. The type of bile duct reconstruction did not influence the 5-year patient and graft survival rates ( p =0.14). Intraductal stents were used in 6%, 100%, and 95% of the CC, CJ, and CD groups, respectively. Biliary strictures were observed more frequently in the CC than in the CJ and CD groups (21% vs. 5% vs. 2%, respectively; p <0.001). Four percent ( p =0.06) in the CC group experienced bile leaks, and no bile leaks were observed among patients with CJ or CD reconstructions. The incidence of cholangitis in the CC, CJ, and CD groups was 1%, 10%, and 5%, respectively ( p =0.10). Overall, patients with CD had the fewest biliary complications ( p =0.01). In the CC group, 2 (2.4%) patients required conversion to CD and 6 (7.3%) required conversion to CJ for bile duct obstruction (9.7%). One patient (2%) in the CD cohort and no patients in the CC cohort required stent removal post-transplantation. CD is considered a safe alternative. Biliary complications were not associated with graft loss or mortality. Postoperative biliary complications are infrequent, suggesting that CD is a suitable and possibly superior type of biliary reconstruction compared to conventional CC or CJ anastomosis.

Duct to duct vs. hepaticojejunostomy for biliary reconstruction in adult living donor right lobe liver transplantation - a systematic review and meta-analysis.

Safety and Outcomes in 100 Consecutive Donation After Circulatory Death Liver Transplants Using a Protocol That Includes Thrombolytic Therapy.

Reduction of Biliary Complication Rate Using Continuous Suture and No Biliary Drainage for Duct-to-Duct Anastomosis in Whole-Organ Liver Transplantation

Duct-to-duct anastomosis (DDA) and hepaticojejunostomy (HJ) are options for biliary reconstruction in patients undergoing adult-to-adult right lobe living donor liver transplantation (ARLDLT), after which biliary anastomotic stricture (BAS) is common as a complication. The risk factors for BAS are not clearly defined. We aimed to determine the rate of post-ARLDLT BAS in our center and its associated factors. In 265 ARLDLT recipients, 55 (20.8%) developed postoperative BAS. The diagnosis was based on clinical, biochemical, histological, and radiological results. The BAS rates were 21.4% (43/201) for recipients undergoing DDA during transplantation, 18.9% (10/53) for recipients undergoing HJ, and 18.2% (2/11) for recipients undergoing both procedures. BAS and non-BAS patients had comparable demographics. The number of graft bile duct openings (P = 0.516) and the size of the graft's smallest bile duct (5 versus 5 mm, P = 0.4) were not significantly different between BAS and non-BAS patients. Univariate analysis showed that the factors associated with postoperative BAS were the recipient warm ischemia time (55 versus 51 minutes, P = 0.026), graft cold ischemia time (120 versus 108 minutes, P = 0.046), stent use (21.8% versus 7.1%, P = 0.001), postoperative acute cellular rejection (29.1% versus 11.0%, P = 0.001), and University of Wisconsin solution use (21.8% versus 7.1%, P = 0.001). Multivariate analysis showed that the cold ischemia time (odds ratio = 1.012, 95% confidence interval = 1.002-1.023, P = 0.014) and acute rejection (odds ratio = 3.180, 95% confidence interval = 1.606-6.853, P = 0.002) were significant factors. The graft survival rates of BAS and non-BAS patients were comparable. One patient required retransplantation for secondary biliary cirrhosis. In conclusion, BAS remains common after ARLDLT regardless of DDA or HJ. The graft cold ischemia time and postoperative acute cellular rejection are significantly associated with postoperative BAS.

Systematic Review and Meta-Analysis of the Outcomes After Hepatic Artery Reconstruction in Pediatric Liver Transplantation Using a Microscope Versus Surgical Loupe

Management of biliary complications after adult-to-adult living donor liver transplantation. Initial experience in a latin american center

Living-related liver transplantation.

Background Recently, liver transplantation settled to be a real breakthrough in surgery as the only curable treatment to deal with fatal liver diseases. Living donor liver transplantation (LDLT) is the only available option in Egypt owing to the inactive deceased donor program. Most of the patients indicated for LDLT do not have the luxury of having an ideal living donor although we have big families in Egypt. Surgeons of recipient’s operation should occupy refined surgical skills and experience to reduce the risk of complications. The incidence of biliary complications (BCs) ranges from 5.3% to 40.6%. Leaks occur in 0% to 21.9% while strictures occur in 3.7% to 25.3%. Duct-to-duct anastomosis (D2D) and hepaticojejunostomy (HJ) are the two most common techniques of bile duct anastomosis in LDLT. D2D is gaining popularity over HJ, because of shorter operative time, fewer septic complications, a better physiologic gastrointestinal function and rapid recovery beside easier endoscopic approach to the reconstructed biliary tract. Patients and Methods The current surgical methodology is a prospective study with nonrandomized convenient sampling that was conducted at Liver Transplantation Unit in Air Forces Specialized Hospital and Nasser Institute for Research and Treatment, Cairo, Egypt, between August 2019 to August 2021. During this study, 40 patients candidate for LDLT was divided into two groups according to type of biliary anastomosis, group A included 20 recipients who had stentless duct-to-duct biliary anastomosis compared to group B including 20 recipients underwent Roux-en-Y hepaticojejunostmy. Results A total of 40 recipients were divided into two equal groups according to biliary reocstruction into group A duct-to-duct biliary anastomosis, and group B Roux-en-Y hepaticojejunostmy. The incidence of biliary related complications was higher in group A reaching 30%, double that recorded in group B (15%, p = 0.262). Upon stratification of those complications, the incidence of biliary leakage was reversed being doubled in group B 10% versus 5% in group A (p = 0.553). After exclusion of seven mortalities (one in group A and 6 in group B) who did not complete the 6 months follow-up period necessary for complete observation of BAS, there was insignificant difference between the two groups. The overall mortality was 17.5% (7 out of 8 recipients), and all died from non-biliary complication related causes. The only recipient died from biliary sepsis following ERCP and stenting for BAS, was included in the results as he died after 5 months from the operation. In a trial to understand the relation between the biliary reconstruction and the complication rate (Table 8), we found that there was a higher frequency of complications in both 1x1 and 2x2 technique in group A (33% each). In contrast, all complication happened in group B was in 1x1 technique. In addition, we could not apply the statement that the higher the number of ducts the higher the rate of complications in the study as 2 ducts grafts represent 66.7% of complications in group A compared to 100% in single duct graft in group B. Conclusion BC is a bottleneck along the path of a successful LDLT as it is multifactorial making it impossible to specify a single predictable risk factor to avoid. The advantages of D2D over HJ; especially the beneficial use of ERCP in management of complications, are buffered by the higher incidence of biliary complication that is involved with D2D. Therefore, we think that surgeons should master both reconstruction techniques and weight the risk-and-benefit case by case.

O446 Aims: Biliary complications remain one of the most serious problems after living donor liver transplantation (LDLT). Hepaticojejunostomy (HJ stomy) has been a standard procedure for biliary recontruction. However, recently, duct-to-duct (DD) anastomosis is used more widely, because DD anastomosis has more physiologic bilioenteric continuity. We performed this study to evaluate safety of various biliary reconstruction for LDLT. Methods: Between January 1999 and December 2002, 147 recipients, > 1 year postoperatively, were enrolled. HJ stomy was performed in 85 cases (57.8%) and DD anastomosis in 62 cases (42.2%). In DD anastomosis, a T-tube was inserted via CBD in 33 cases(53.2%), a internal stent tube was pushed upward in the anastomosis throughout CBD in 7 cases (11.3%), and no drainage tube was used in 22 cases (5.5%). Results: Among 147 cases, 30 biliary complications developed (20.4%). In HJ stomy, the incidence of complication was 8.2% (7/85). The complications in HJ stomy consisted of 3 cases of bile leak, 4 cases of biliary stricture. In DD anastomosis, the incidence of complication was 37.1% (23/62). The complication rate in cases using a internal stent was 71.4% (5/7). Complications consisted of 4 cases of bile leak and one case of biliary stricture. The complication rate in cases using a T-tube was 33.3% (11/33). Complications consisted of 6 cases associated with tube removal, 5 cases of biliary stricture. The complication rate in cases without biliary drainage tube was 31.8% (7/22). Complications consisted of one accidental ligation of right posterior duct and 6 cases of biliary stricture. The complication rate was lower in HJ stomy than in DD anastomosis (p<0.05). Surgical correction of complications was more frequently needed in complications of HJ stomy than in that of DD anastomosis. Reoperation rate was 28.5% (3/7) in complications of HJ stomy. Conversion rate of DD anstomosis to HJ stomy was 8.7% (2/23). In cases of DD anastomosis without a stent, all complications were corrected by radiologic intervention. However there was no statistical significance Conclusions: In LDLT, the complication rate of various biliary reconstructions was 20.4%. The complication rate of HJ stomy was lower than that of DD anstomosis. For further evaluation, a controlled radomized study was needed.

Biliary Tract Complications after Orthotopic Liver Transplantation: Still the “Achilles Heel”?

A179 Introduction: The routine biliary reconstruction for patients who undergo orthotopic liver transplantation (OLT) for primary sclerosing cholangitis (PSC) is hepaticojejunostomy (HJ). Some articles have suggested the use of a choledocho-choledochostomy (CC) as a valid alternative for the biliary anastomosis. Objectives: To analyze the biliary complications rate in patients undergoing OLT for PSC with CC reconstruction. Methods: From 1988 to 2003, 1057 patients were transplanted in our institution, twenty-one of them (2 %) due to primary sclerosing cholangitis. In five of them (23%) biliary reconstruction was made by choledocho-choledochostomy (CC) with T-tube, and in the other sixteen (76.2%) by hepaticojejunostomy (HJ). Mean follow-up was 7 years (SD 4.86 years). Results: No differences in sex, age, preservation solution, cold ischaemia time and postoperative arterial thrombosis rate were found between both groups. The overall biliary complication rate was 33% (7/21). Eighty percent of patients who underwent CC anastomosis had biliary complications (1 cholangitis and 3 biliary leaks, two of them requiring surgical intervention). Only 18,7% of the patients with HJ had biliary complications (2 cholangitis and a biliary leak). These differences were not significant. Hospital stay was similar (CC 22 days, HJ 35.5 days) (P=NS). Conclusions: Despite the fact that the differences among the two groups are not significant, there is a trend towards a higher incidence of biliary complications in the CC group.

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 and A further advantage of MMF is to facilitate early steroid withdrawal and Drug The main side effects of MMF are dose dependent gastrointestinal and bone suppression which usually resolve after dose reduction MMF also has been associated with a slightly increased frequency of and lymphoproliferative as with any immunosuppressive regimen. and increase MPA may with the enterohepatic circulation of MPA, and therefore its concentration in the may also decrease MPA levels as may the administration of that intestinal absorption of MMF with CSA increased MMF dosage compared with children on TRL therapy but high TRL concentrations may also decrease MPA potential toxicity or loss of MPA monitoring is required where dose or of CSA and TRL are being and where drug interactions are Pharmacodynamics SRL is a from the with potent immunosuppressive Despite structural to TRL, as well as the intracellular SRL from its mechanism is to T-cell activation by of CNIs with IL-2 This is achieved by inhibition of the target of by the resulting in the inhibition of which is for T-cell activation and proliferation is experimental data that SRL has and activity Pharmacokinetics SRL is a highly drug that is absorbed rapidly from the gastrointestinal It is metabolized by the CYP3A enzyme family and therefore has a drug profile similar to the CNIs (Table 2). Its half-life is long hours) and and interindividual to a poor correlation of the dose to either C0 or AUC SRL levels are known to significantly increase during administration of CSA not and dosage 4 hours after CSA is recommended SRL 50% reduction in CSA exposure studies showed correlation between C0 and AUC and that blood peak concentrations are within 2 to 3 hours after administration of a single oral dose C0 values were correlated with clinical with C0 greater than 15 associated with increased incidence of adverse effects and values of 6 to 12 reported to low rates of graft rejection and toxicity Dosing and Monitoring dosing for SRL is still under A single daily dose to 15 has been well tolerated In adults, is given as one time oral dose of 6 to by daily dosing of 2 to monitoring of SRL is not because of the long half-life of the drug tissue the first SRL will not be obtained day 4 of therapy. monitoring C0 twice for the first month and for the month is a to 15 After the second drug levels should be in children to growth and as by in with drugs CYP3A in CSA in or of gastrointestinal or toxicity Clinical Efficacy The efficacy of SRL in solid organ transplantation was shown in the renal transplant prospective studies in renal graft recipients revealed that immunosuppression is with CSA-based immunosuppression in acute rejection and patient and graft survival uncontrolled studies in LT recipients have shown SRL to be an effective agent when with a CNI (Table series that effects of SRL permit LT with low rates of acute rejection using CNI at low doses the for toxicity It early steroid withdrawal low rates of acute rejection when used in with CNI of SRL were during rescue treatment after chronic rejection and as an effective agent in immunosuppressive regimens in stable LT patients after their withdrawal to and to use SRL as a single primary immunosuppressive agent in a small series of LT recipients resulted in a high rate of acute rejection that SRL should be used in a Studies on use of interleukin-2 receptor antibodies in a primary immunosuppressive regimen in pediatric liver transplant activity of SRL achieved by in tissue through reduction of growth may a specific for using SRL after transplantation for the greatest potential benefit of SRL in LT recipients is its lack of and The most adverse effects of SRL include and but also are and particularly of the the and efficacy of SRL in liver allograft is not and the Food and Drug Administration has not approved SRL for use in LT, several trials have been reported (Table large multicenter trial to SRL therapy in LT recipients was as a of an increased incidence of In other studies have shown no higher incidence of and a benefit of SRL in the prevention of controlled studies are required to SRL has important effects. is but no evidence that SRL in transplant recipients the basis of these higher oral doses and blood levels should be because they may be associated with a higher incidence of complications, and the drug does have effects that could studies are required on the influence of SRL on complications after Studies on use of sirolimus and low dose calcineurin inhibitor in a primary immunosuppressive regimen in adult liver transplant T cells in acute rejection are by the expression of activation such as the IL-2 The complex of at and is expressed on the of T cells, the other are expressed on T cells Therefore, target therapy appears to be a for specific immunosuppression. results with IL-2 appeared but a significant was the short half-life and the of the drugs within 2 posttransplant. these and of these were are less and have much and Dosing is a human monoclonal Ab that binds but does not the IL-2 and has a half of approximately 11 days in renal transplant patients is a Ab that less than and has a half-life of approximately days in renal transplant recipients studies in adult renal transplant recipients, based on dosage regimen for on days 0 and and doses regimen for mg/kg on day at and have receptor suppression for approximately 3 to 4 for and to 10 for The of receptor suppression and is significant beyond 4 is The half-life of was lower in LT than renal transplant recipients and clearance through or by extensive postoperative blood loss in LT patients was suggested as the administered as dosage regimen IL-2 suppression of days and to days in and a half-life of days In children, is given as a regimen of 10 or on day 0 or within 6 hours and day For a of dosing regimens have been from a single dose of 2 mg/kg to and triple dosage regimens It is that a regimen of 1 mg/kg on day 0 and 4 after will receptor for to It has been suggested that dose adjustments or further dosing is for patients with or when no or only a low level of CNI drugs are being used Studies with have that is the effective serum concentration required to IL-2 The concentration of required to inhibit IL-2 proliferation and cells is 1 with at trough levels of to 10 Clinical Efficacy are trials with both in adult LT recipients. The of induction therapy with and but without was in a in LT The was after the first patients acute rejection. In the patients received and corticosteroids with introduction of low dose on days The most important acute rejection appeared to be the in with of patients receiving CNI after posttransplant day acute rejection of