16- https://doi.org/10.1097/01.mpg.0000172260.46986.11
Immunosuppression in Pediatric Liver and Intestinal Transplantation: A Closer Look at the Arsenal
Translate Article 
Take Notes 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
- Research Article
- 34
- 10.1016/s0168-8278(03)00428-8
- Sep 6, 2003
- Journal of Hepatology
Immunosuppressive therapy in liver transplantation
- Research Article
- 29
- 10.1111/ajt.15789
- Feb 6, 2020
- American Journal of Transplantation
Early reduction of regulatory T cells is associated with acute rejection in liver transplantation under tacrolimus-based immunosuppression with basiliximab induction.
- Research Article
- 1
- 10.1097/00005176-200210003-00010
- Oct 1, 2002
- Journal of Pediatric Gastroenterology and Nutrition
RATIONALE In 1998, a total of 522 liver transplants, or approximately 12% of such operations in the US, were performed in patients younger than 18 years of age (1). For these children as for adults who underwent liver transplantation, 1-year survival rates approached 85%, the result of improvements in surgical technique, immunosuppression and antiviral therapy. The findings of studies in adult populations cannot be generalized to children because of differences in the indications for transplantation, as well as differences in surgical, infectious and developmental complications. A number of factors hamper pediatric studies. Even at the largest centers, only 30 to 40 children undergo transplantation each year and the population is heterogeneous. Consequently, individual transplant centers do not care for populations of sufficient size to identify interventions that improve outcome. Furthermore, with pharmacotherapeutic and surgical advances, the standard of care has evolved. The interpretation of studies performed over time at any single center is subject to the biases introduced by changes in care practices. Three major areas of research are considered of primary importance: tolerance induction, evaluation of outcome after liver transplantation, and post-transplant lymphoproliferative disease. In addition, there are three major research areas that may be considered a rank below: nonimmune graft injury, intestinal graft rejection and hepatocyte transplantation. AREAS OF EMPHASIS Evaluate Strategies to Induce Tolerance Research Goals Tolerance is classically defined as donor-specific immuno-nonresponsiveness and is manifest by long-term allograft function, without evidence of immunologic injury, maintained in the absence of immunosuppression (2). Full immunoresponsiveness to non-donor-derived antigens is preserved: animal studies have demonstrated the ability to fully reject a graft from a different donor as well as acceptance, without immunosuppression, of a second graft from the original donor. To date, true tolerance has been achieved in some small rodent models, but it is proving difficult to achieve consistently in large primate models. Current immunosuppressive strategies are nonspecific and, as such, associated with significant long-term risks of malignancy and infection. The nonimmunologic toxicities of current therapeutic modalities are substantial. With prolonged use, debilitating and life-threatening complications, including nephrotoxicity, neurotoxicity, bone disorders and cardiovascular disease, may occur. This has spurred research efforts to explore the mechanisms and clinical applications of tolerance induction. Furthermore, the problem of chronic rejection, which most likely is mediated by immune pathways different from those of acute rejection, has not been prevented by current immunosuppressive regimens (3). With successful tolerance induction strategies, long-term immunosuppressive drugs can be avoided. Such avoidance is of particular urgency in pediatric transplant recipients, who currently face the prospect of many decades of immunosuppressive drug use. Efforts to decrease long-term immunosuppression, or even consider discontinuation of immunosuppressive agents, are severely handicapped by lack of a reliable test to measure the recipient's degree of immunoresponsiveness to the graft. Without such a tolerance assay, random discontinuation of immunosuppressive therapy in stable patients is fraught with uncertainties. Research Goals The principal mechanisms of tolerance—anergy or depletion of alloreactive T cells, immuno-regulation and chimerism—are now providing promising strategies for clinical application. T cells are an absolute requirement for the rejection response. Cell surface markers that are capable of initiating co-stimulation are prime targets for new blockade approaches to modulate the immune response. Monoclonal antibodies to these targets are being developed, many of which are humanized to avoid induction of a neutralizing human antibody response. To advance this critically important field, the following areas of research must be targeted and supported: Increased application of immunomodulatory strategies to induce tolerance in large primate models Clinical trials in pediatric populations. Even early human trials of tolerance-inducing strategies must include pediatric recipients, while recognizing that the immune response and its regulation may be different in children Development of biologic markers to measure donor-specific immune response. Such markers will not only assess outcome in studies designed to induce tolerance but also, in the short term, provide important information for the tailoring of current immunosuppressive regimens to individual patients, to avoid over- and under-immunosuppression Research Strategies Critical to these efforts are basic science investigations that will further our understanding of T-cell signaling and activation. Clinical trials will require the participation of multiple transplant centers. Projected Timetable and Funding Requirements Basic science and clinical research initiatives to achieve tolerance will require a substantial and ongoing financial commitment. These initiatives provide an ideal opportunity for partnering between federal agencies and private groups, including the pharmaceutical industry. This research area is an extremely important frontier for young investigators. The infrastructure needed to support such studies includes data-gathering and analysis mechanisms to allow multicenter trials to be conducted. Funding for such collaborative multicenter databases, specific to the special outcomes and requirements of pediatric liver and intestinal transplant recipients, is critical. Prospectively Evaluate Outcome Measures After Pediatric Liver Transplantation Advances in immunosuppressive therapy and surgical techniques have improved graft and patient survival rates as well as expanded access to donor organs for pediatric liver transplant recipients. The improved rates have, in turn, resulted in greater acceptance of the procedure by patients, parents and physicians. The number of centers performing pediatric liver transplantation has increased as a direct result of greater patient and physician enthusiasm for the procedure, while the number of pediatric transplants has remained constant. Although the increased number of transplant centers likely has improved access to the procedure and proved convenient for patients and their families, the experience at each center has been substantially diluted. Increasing donor demand adversely affects donor availability for pediatric recipients. In addition, there is increasing pressure at present from public and private payers to raise efficiencies and cut costs. These factors provide a substantial impetus for pediatric transplant centers to examine the outcomes achieved in order to provide adequate stewardship for scarce donor resources and utilize dwindling financial resources most effectively (4). Unfortunately, the steady dilution in pediatric transplant experience precludes all but the crudest analysis of transplant outcomes. Research Goals It is recommended that a large multicenter transplant registry be developed that would prospectively collect data from all pediatric transplant centers. Such a database is essential for the accurate analysis of patient outcomes and for the development of innovations that might improve these outcomes in the future. Data from the multicenter pediatric transplant registry would be analyzed to determine the: A) Long-term graft and patient survival for pediatric transplantation, stratified by disease. Data on survival are currently available only for a few pediatric liver diseases. However, less common liver diseases that are considered potential indications, such as metabolic diseases, collectively account for about 30% of pediatric transplants. For many of these disorders, only anecdotal experience of short-term outcomes at a single center has been published. Establishment of a registry detailing the results of transplantation would allow for a more accurate assessment of the effectiveness of transplantation. These data, for example, would help determine the optimal timing of transplantation and the appropriateness of transplantation as a treatment option. B) Best methods of surgical and medical management. With dispersion of the pediatric transplant experience, local variations have developed in both the surgical procedure and postoperative care, including the use of immunosuppression. Some of these local idiosyncrasies may add to the overall cost of the procedure. Since there is currently no method to track the outcome of these various approaches, their effectiveness cannot be determined. The analysis of outcomes resulting from these management strategies, with comparison to outcomes in the entire data set, would be a first step in determining whether there is an optimal approach to operative and postoperative management. C) Long-term growth potential and long-term development potential of patients undergoing liver transplantation. Information regarding these issues is currently lacking and requires the collection of data to track somatic growth, reproductive capabilities, and educational and occupational achievements relative to the clinical characteristics of patients undergoing transplantation. Acquisition of this information would help to determine the optimal timing of the transplant procedure, and would allow for comparison of transplantation with other management strategies (5). For example, if it were shown that otherwise stable patients with cholestatic liver disease suffered irreversible compromise of growth or intellectual achievement over time, early transplantation would be justified. D) Long-term effects of immunosuppressive therapy. Several complications of standard immunosuppressive medications have been documented in children and adults. These include increased lipid levels, hypertension, decreased renal clearance, altered glucose metabolism, compromised growth and diminished bone accretion (6–8). The impact of these adverse effects is substantially greater in children than in adults because of the longer period of exposure to the drugs. The incidence of severe injury leading to potentially life-threatening conditions such as renal failure, heart disease or osteoporosis is not known. A determination of the incidence of these adverse effects, and the factors that predispose to their development, would be an important initial effort in devising strategies to reduce drug-induced organ damage. E) Long-term quality of life of children and their families after liver transplantation. The goal of transplantation is to improve the quality, as well as the quantity, of the patient's life. Recently, accurate, validated tools have been developed to assess pediatric quality of life. A large multicenter study utilizing these tools to evaluate the effectiveness of liver transplantation in reaching this goal is essential. As part of this study, children and their families would be followed over the long term, data would be stratified by specific diseases, and management strategies could be identified that yield the best outcomes. F) Long-term costs of transplantation. Anticipated costs for individual liver transplant recipients are currently difficult, if not impossible, to assess. Factors influencing cost include regional differences in overall cost of medical care, the United Network for Organ Sharing (UNOS) status of the patient at the time of transplantation, the number of comorbid conditions, and the type of graft. A database that tracks expenditures in addition to medical variables would be a first step in developing an accurate projection of costs for individual patients. Long-term follow-up of patient outcomes and cumulative associated costs would enable development of realistic cost-benefit analyses for pediatric transplantation. Research Strategies To achieve the above goals, a registry encompassing the majority of North American pediatric liver transplant recipients needs to be developed. Data must be collected in a prospective, standardized manner and analyzed in a timely and statistically valid fashion. Individual patients must be followed until adulthood. The ultimate goal of such a registry would be to determine the expected outcomes of liver transplantation for specific recipients and to identify factors that would influence the likelihood of achieving these outcomes. Validated tools need to be utilized or developed to assess some of these outcomes. Comparable experience in the pediatric oncology community has demonstrated the value of such a registry for determining therapeutic outcomes and developing new strategies to improve outcomes. An industry-funded pediatric liver transplant registry called SPLIT (S tudies in P ediatric L iver T ransplantation) currently collects data from 34 centers in Canada and the US, representing approximately 25% of the procedures performed annually. We propose expanded funding of the existing database to enable recruitment of additional centers to capture a minimum of 75% of the transplants performed each year. In addition, prospective studies evaluating specific outcomes are recommended. It is only through acquisition and analysis of these data that true measurements of the long-term effectiveness of liver transplantation will be achieved. Projected Timetable and Funding Requirements Funding for individual centers is needed to expand the existing SPLIT database to encompass the majority of pediatric liver transplant centers. Funding would largely be directed at support for transplant coordinators who gather the large amount of data required and for data entry personnel responsible for inputting the data. A small part of the funds would be allocated to a central data collection agency. Evaluate Interventions to Prevent and Treat Post-Transplant Lymphoproliferative Disease Post-transplant lymphoproliferative disease (PTLD) occurs in up to 11% of pediatric liver transplant recipients and up to 25% of pediatric intestinal transplant recipients. The associated mortality rate can be as high as 20% to 60%. In pediatric patients, more than 85% of PTLD is related to Epstein-Barr virus (EBV) infection and PTLD presents as a spectrum of disease ranging from benign B-cell hyperplasia to malignant lymphomas (9). Patients who are EBV naive and receive an organ from an EBV-positive donor, especially those being treated with increased levels of immunosuppressive agents for resistant rejection, are at high risk of developing PTLD (10). Infants and toddlers, who constitute 50% of the pediatric liver transplant population, are usually EBV naive. Up to 15% of high-risk liver transplant recipients will develop PTLD. More than 75% of high-risk patients acquire the virus within the first year of life. For children, especially those younger than 2 years of age, PTLD not only can be lethal but also can critically affect quality of life and graft function. It has been hypothesized that the outcome of EBV infection in pediatric transplant recipients reflects a balance between EBV-driven B-cell proliferation and the activity of EBV-specific cytotoxic T cells. If this hypothesis is true, then therapy that enhances the EBV-specific T-cell response or decreases B-cell proliferation should prevent PTLD. Prevention and preemptive treatment strategies include polymerase chain reaction (PCR) monitoring of the peripheral blood for the EBV genome, combined with antiviral therapy and reduction of immunosuppression with the first evidence of EBV infection. Treatment requires stopping T cell-directed immunosuppression so that immune surveillance by EBV-specific cytotoxic T cells is restored. Transplant physicians also use medications that inhibit viral replication and high-titer cytomegalovirus (CMV) globulin to prevent and treat PTLD. The efficacy of antivirals and immunoglobulin is difficult to assess because reduction of immunosuppressive therapy is almost always initiated simultaneously. However, the enhanced immune response that results from reduced immunosuppression is nonspecific and may precipitate allograft rejection. Research Goals Interventions need to be tested that can prevent or treat PTLD in pediatric liver transplant recipients by shifting the balance between B-cell proliferation and activation of EBV-specific cytotoxic T cells. Basic research is needed to develop: A reproducible method to measure EBV-specific cytotoxic T-cell activity; and A method for in vitro activation of recipient-derived EBV-specific T cells, including T cells from EBV-naïve recipients. The T cells can then be reinjected into the recipient at the time of diagnosis of PTLD to restore EBV-specific cytotoxic T cell competence (11). Clinical trials are needed to: Evaluate preemptive therapy that enhances EBV-specific cytotoxic T-cell activity and prevents development of PTLD Study the role of serial EBV PCR monitoring of the peripheral blood in preemptive therapy Determine the efficacy of standard treatment approaches (reduced immunosuppression, antivirals, hyperimmune globulin) in patients with PTLD Determine the efficacy of treatment with monoclonal antibodies directed against B cells or chemotherapy in restoring the balance between B-cell proliferation and EBV-specific T-cell response in patients who fail to respond to preemptive or standard therapy. Research Strategies An analysis of the SPLIT registry shows that 120 children annually meet the criteria for entry into the registry. It is known that up to 80% of high-risk patients are infected with EBV each year and that as many as 12% develop PTLD. We predict that 50% of patients with PTLD will not respond to standard therapy. A multicenter trial to determine optimal novel treatment is necessary because the number of patients at even the largest transplant centers is too small to achieve adequate power. Projected Timetable and Funding Requirements One or two funded investigators will be required to address each basic research goal. The clinical research goals will be aided by creation of a clinical trials network linking multiple centers. Evaluate Treatment Strategies for Minimizing Nonimmune Graft Injury Liver allografts are a precious commodity since demand far exceeds supply. To use existing resources efficiently, initial graft function must be optimized. When the graft does not function, or initial function is poor owing to reperfusion injury, there is an increased risk of perioperative morbidity and graft loss, as well as greater health resource utilization. It is increasingly recognized that nonimmune injury to the allograft is associated with significant short-term and long-term consequences. Nonimmune graft injury results from the effects on the donor organ of brain death itself, ischemia/reperfusion injury and preexisting injury in the graft. With a better understanding of the underlying mechanisms, preventive strategies can be designed. There are several compelling reasons why progress in this area of research is important. First, preventing or ameliorating the injury induced by brain death and ischemia/reperfusion is likely to improve early cadaveric graft function and reduce the need for retransplantation due to primary nonfunction or poor initial function. In view of the ongoing cadaveric donor shortage, advances in this area are of particular importance. In addition, improved graft protection may allow the successful use of more marginal donors, which would further expand the cadaveric donor pool. Second, it is now known that the nonspecific inflammatory response induced by nonimmune injury itself up-regulates the immune response to the graft (12). The risk of acute rejection may be increased, but of greater importance is recent evidence suggesting that chronic rejection may be linked to early nonimmune injury. Third, an understanding of the regenerative response of the liver after injury is critically important with the increasing use in children of segmental liver grafts, particularly those from cadavers. This research is also relevant to liver donor grafts. Interleukin-6 is a key cytokine involved in activating transcription factors, such as JAK kinase and STAT3, which activate hepatocyte cell division. Current immunosuppressive drugs may be detrimental to some of these responses; for example, steroids inhibit liver regeneration. Research Goals Research efforts are needed to develop strategies for minimizing nonimmune injury and thereby optimizing early graft function. Such efforts will improve the cadaveric donor supply by allowing more cadaveric organs to be split. It is also important to promote the regenerative response of the segmental liver graft for a successful outcome after pediatric split transplantation. Identify Markers and Develop Diagnostic Tests for Rejection Following Intestinal Transplantation Research Goals Isolated intestinal grafts constitute about one half of the 50 to 100 intestinal transplants that are performed each year in the US. Recent reports have indicated that acute rejection of the isolated graft is virtually universal and an important cause of graft loss. The incidence and severity of rejection, although somewhat less in cases of combined liver-intestinal transplantation, is greater than occurs with isolated liver grafts. Intestinal allografts are also susceptible to chronic rejection, which occurs rarely with liver grafts. Rejection of intestinal grafts is difficult to diagnose and treat. Unlike with liver and kidney transplantation, there is no simple blood test to detect when the small intestine initiates the process of rejection. Tissue diagnosis is often difficult as the process can be patchy. A late diagnosis often results in loss of an intestinal graft. Studies are needed to: Evaluate histologic markers for rejection. Special staining techniques may be used based on an understanding of the mechanisms underlying rejection. Develop functional tests to assess changes in intestinal function that correlate well with rejection. Permeability studies have been evaluated for this purpose, but results were nonspecific (13). Identify serum proteins, enzymes, and other markers that might be elevated early during the course of rejection (14). Research Strategies Several complementary approaches may be required. Studies can be conducted only at centers where large numbers of intestinal transplant procedures are performed. Projected Timetable and Funding Requirements These studies are likely to be an ongoing project. The cost of part-time technical assistance, specialized nursing support for clinical aspects of the research, and data analysis may be significant. Supplemental immunologic studies, if included, could easily raise estimates of the total annual cost. Broaden the Clinical Applications of Hepatocyte Transplantation Hepatocyte transplantation (HTX) continues to evolve as a potential therapeutic adjunct to liver transplantation. By providing normal hepatocytes to patients with a liver-related metabolic defect, HTX can improve metabolism (15). HTX can also as a in liver patients liver transplantation, providing a sufficient to metabolic The development of HTX as a treatment after decades of basic research in liver cell issues the of hepatocytes and needed to be With successful hepatocytes can be and centers for use in the treatment of patients with liver Research Goals To the applications of further studies are to methods of of a number of cells needed for successful a single or are is the optimal of or for patient patients with metabolic disease for In do criteria for patients with acute chronic liver time of in to a patient's clinical might during of liver early In addition, studies are needed to address the of availability of methods must be developed that enable hepatocytes to in that has been the number of hepatocytes available for transplantation will of the availability of new Research Strategies To achieve these research goals, multicenter clinical trials as well as basic research are It is important to support the creation of regional centers for the of research will also be enhanced by the development of animal models of liver cell transplantation. The population of long-term of liver transplantation has by the number of transplant procedures performed each year. In the cost of the liver transplant procedure and associated is at about For each year after a successful liver transplantation, direct health care costs are to to of the cost of transplantation and Consequently, after the cumulative cost of graft function and in a population of long-term is to the cost of the liver transplantation procedure. on these it is that is each year on liver transplantation in the pediatric for the procedures and an amount to graft function and in the impact of pediatric transplant on total health care costs will increasingly since the potential for years of life for a undergoing transplantation is greater than that for a The and cost to the is more difficult to There is loss of when patients care for their children through long of and follow-up may their and health while the medical needs of children during the studies are virtually in children and parents after liver or intestinal transplantation. The of children who undergo transplant procedures will affect their ability to and of the impact of liver and intestinal transplantation has not been
- Research Article
- 21
- 10.1111/j.1523-1755.2005.09923.x
- Dec 1, 2005
- Kidney International
Immunosuppressive treatment and progression of histologic lesions in kidney allografts
- Research Article
- 9
- 10.1053/j.ackd.2009.08.004
- Dec 10, 2009
- Advances in Chronic Kidney Disease
Kidney Transplantation in Patients With HIV Infection
- Research Article
- 10.1128/spectrum.01862-25
- Jan 6, 2026
- Microbiology spectrum
Epstein-Barr virus (EBV) DNAemia poses a significant risk to transplant recipients, leading to Post-transplant lymphoproliferative disorder (PTLD). This study aims to determine the occurrence of EBV DNAemia among liver transplant (LT) recipients and analyze its association with various clinical parameters. Retrospective data search on 801 patients who underwent LT from January 2015 to December 2024 was performed. Of these, 257 recipients with available EBV DNA test records post-transplant were included and divided into EBV DNAemia and non-EBV DNAemia group. Various pre-transplant (age, MELD/PELD score, transplant type, EBV/CMV serostatus), transplant (cold/warm ischemia time, blood transfused), and post-transplant factors (EBV DNAemia, CMV infection, rejection, and immunosuppressant) were compared in both groups using univariate and multivariate analysis. Out of 257 cases, 138 (53.7%) were adults with a median age of 29 (IQR: 4.5-47) years. EBV DNAemia group included 50 (19.5%) cases with median age 2 (IQR: 1-5) years, majority (56%) classified as high-risk. The median time of EBV DNAemia detection since LT was 319 (IQR: 190-732) days with median viral load of 3.33 (IQR: 2.85-3.80) log10 copies/mL. PTLD developed in three cases (both high/intermediate risk). Non-EBV DNAemia group included 207 (80.5%) cases, with median age of 36 (IQR: 11-49) years, primarily belonging to intermediate risk. Age and pre-transplant EBV serostatus were found to be associated with EBV DNAemia on multivariate analysis. Routine monitoring of EBV DNAemia in both adult and pediatric LT recipients, regardless of pre-transplant serostatus, is crucial for early detection and management of EBV DNAemia/associated complications.IMPORTANCEThere is a significant lack of comprehensive studies on the prevalence and clinical impact of EBV DNAemia among liver transplant (LT) recipients in India. The absence of standardized monitoring and management protocols across Indian transplant centers further adds to inconsistencies in clinical practices, leading to challenges in early detection and intervention. Existing research primarily focuses on the high-risk pediatric renal transplant recipients with limited data available for adult LT recipients. This study aims to address these gaps by providing crucial insights into EBV DNAemia among Indian LT recipients and its association with various clinical parameters.
- Research Article
- 482
- 10.1002/lt.23566
- Dec 28, 2012
- Liver Transplantation
Michael R. Lucey, Norah Terrault, Lolu Ojo, J. Eileen Hay, James Neuberger, Emily Blumberg, and Lewis W. Teperman Division of Gastroenterology and Hepatology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI; Gastroenterology Division, Department of Medicine, University of California San Francisco, San Francisco, CA; Division of Nephrology, Department of Medicine, University of Michigan, Ann Arbor, MI; Mayo Clinic, Rochester, MN; Liver Unit, Queen Elizabeth Hospital, Birmingham, United Kingdom; Division of Infectious Diseases, University of Pennsylvania School of Medicine, Philadelphia, PA; and Department of Surgery, NYU Transplant Associates, New York, NY
- Research Article
- 29
- 10.1097/mpg.0000000000002592
- Mar 1, 2020
- Journal of Pediatric Gastroenterology and Nutrition
Observed long-term outcomes no longer reflect the survival trajectory facing pediatric liver transplant (LT) recipients today. We aimed to use national registry data and parametric models to project 20- and 30-year post-transplant outcomes for recently transplanted pediatric LT recipients. We conducted a retrospective cohort study of 13,442 first-time pediatric (age <18) LT recipients using 1987 to 2018 Scientific Registry of Transplant Recipients data. We validated the proposed method (ie, to project long-term patient and graft survival using parametric survival models and short-term data) in 2 historic cohorts (1987-1996 and 1997-2006) and estimated long-term projections among patients transplanted between 2007 and 2018. Projections were stratified by raft type, recipient age, and indication for transplant. Parsimonious parametric models with Weibull distribution can be applied to post-transplant data and used to project long-term outcomes for pediatric LT recipients beyond observed data. Projected 20-year patient survival for pediatric LT recipients transplanted in 2007 to 2018 was 84.0% (95% confidence interval 81.5-85.8), compared to observed 20-year survival of 72.8% and 63.6% among those transplanted in 1997 to 2006 and 1987 to 1996, respectively. Projected 30-year survival for pediatric LT recipients in 2007 to 2018 was 80.1% (75.2-82.7), compared to projected 30-year survival of 68.6% (66.1-70.9) in the 1997 to 2006 cohort and observed 30-year survival of 57.5% in the 1987 to 1996 cohort. Twenty- and 30-year patient and graft survival varied slightly by recipient age, graft type, and indication for transplant. Projected long-term outcomes for recently transplanted pediatric LT recipients are excellent, reflective of substantial improvements in medical care, and informative for physician-patient education and decision making in the current era.
- Research Article
- 20
- 10.1002/lt.21274
- Jan 1, 2007
- Liver Transplantation
There are few pharmacokinetic data for mycophenolate mofetil (MMF) when used in combination with cyclosporine (CsA) in pediatric liver transplant recipients. The aim of this study was to assess the pharmacokinetics of MMF in stable pediatric liver transplant patients and estimate the dose of MMF required to provide a mycophenolic acid (MPA) exposure similar to that observed in adult liver transplant recipients receiving the recommended dose of MMF (target area under the plasma concentration-time curve from 0 to 12 hours [AUC(0-12)] for MPA of 29 mug.hour/mL in the immediate posttransplantation period and 58 microg x hour/mL after 6 months). A 12-hour pharmacokinetic profile was collected for 8 pediatric patients (mean age 20.9 months) on stable doses of MMF and CsA who had received a liver transplant > or = 6 months prior to entry and who had started on MMF within 2 weeks of transplantation. Mean MMF dosage was 285 mg/m(2) (range, 200-424 mg/m(2)). Of 8 patients, 7 had a MPA AUC(0-12) (range, 11.0-37.2 microg x hour/mL) well below the target. One patient had an AUC(0-12) > or = 58 microg x hour/mL but was considered an outlier and was excluded from analyses. Mean MPA AUC(0-12) and maximum plasma concentration values were 22.7 +/- 10.5 microg x hour/mL and 7.23 +/- 3.27 microg/mL, respectively; values normalized to 600 mg/m(2) (the approved pediatric dose in renal transplantation) were 47.0 +/- 21.8 microg x hour/mL and 14.5 +/- 4.21 microg/mL. In conclusion, assuming that MPA exhibits linear pharmacokinetics, when used in combination with CsA, a MMF dose of 740 mg/m(2) twice daily would be recommended in pediatric liver transplant recipients to achieve MPA exposures similar to those observed in adult liver transplant recipients. This finding should be confirmed by a prospective trial.
- Research Article
- 54
- 10.1016/j.jhep.2010.12.001
- Dec 9, 2010
- Journal of Hepatology
Immunosuppression in liver transplant recipients with renal impairment
- Front Matter
- 16
- 10.1016/j.jhep.2006.02.002
- Feb 17, 2006
- Journal of Hepatology
Immunosuppression and outcomes of patients transplanted for hepatitis C
- Research Article
- 5
- 10.1128/spectrum.00460-21
- Oct 6, 2021
- Microbiology Spectrum
ABSTRACTMethicillin-resistant Staphylococcus aureus infections are a significant cause of morbidity and mortality in pediatric liver transplant (LT) recipients. Physiological changes following LT may affect vancomycin pharmacokinetics; however, appropriate dosing to achieve sufficient drug exposure (i.e., 24-h area under the concentration-time curve [AUC24]/MIC ≥ 400) in pediatric LT recipients has not been reported. This retrospective pharmacokinetics study of LT recipients aged <18 years utilized data on patient characteristics with vancomycin concentrations and dosing information obtained from electronic medical records. Population pharmacokinetics analysis was conducted by nonlinear mixed-effects modeling with the Phoenix NLME software. Potential covariates were screened with univariate and multivariate analysis. Monte Carlo simulations were performed using the final model to explore appropriate dosing. The study included 270 pharmacokinetics profiles encompassing 1,158 concentrations measured in 161 patients. The median age was 13.3 (interquartile range, 7.6 to 53.5) months, serum creatinine (sCr) was 0.16 (0.12 to 0.23) mg/dl, and days from LT (DFLT) was 17 (6 to 31). Multivariate analysis demonstrated that lower sCr and shorter DFLT were associated with higher clearance. By post hoc estimation, the average clearance and volume of distribution were 0.18 liters/h/kg and 1.01 liters/kg, respectively. The Monte Carlo simulations revealed that only 16% of patients achieved an AUC24/MIC of ≥400 with the assumed vancomycin MIC of 1 μg/ml. DFLT and sCr were significant covariates for vancomycin clearance in pediatric LT recipients. Standard vancomycin dosing may be insufficient, and higher or more frequent dosing may be required to achieve an AUC24/MIC of ≥400 in pediatric LT recipients with normal renal function.IMPORTANCE We evaluated vancomycin pharmacokinetics in pediatric LT recipients and developed a population pharmacokinetics model by considering various factors that might account for alterations in vancomycin pharmacokinetics. Our analyses revealed that lower serum creatinine levels and a shorter duration from the day of LT were associated with higher vancomycin clearance and led to subtherapeutic drug exposure. We also performed Monte Carlo simulations to determine the appropriate dosing strategy in pediatric LT recipients, which revealed that a standard vancomycin dosing might be insufficient and that higher or more frequent dosing might be necessary to achieve an AUC24/MIC of ≥400 in pediatric LT recipients with normal renal function. To the best of our knowledge, this is the first study to assess vancomycin pharmacokinetics in pediatric LT recipients by population pharmacokinetics analysis.
- Research Article
- 60
- 10.1002/lt.23769
- Dec 12, 2013
- Liver Transplantation
Racial and socioeconomic disparities exist in liver transplantation (LT) outcomes among adults, but little research exists for pediatric LT populations. We examined racial differences in graft survival and mortality within a retrospective cohort of pediatric and young adult LT recipients at a large children's transplant center in the Southeast between 1998 and 2011. The association between race/ethnicity and rates of graft failure and mortality was examined with Cox proportional hazards models that were adjusted for demographic and clinical factors as well as individual-level and census tract-level socioeconomic status (SES). Among the 208 LT recipients, 51.0% were white, 34.6% were black, and 14.4% were other race/ethnicity. Graft survival and patient survival were higher for whites versus minorities 1, 3, 5, and 10 years after transplantation. The 10-year graft survival rates were 84% [95% confidence interval (CI) = 76%-91%] for white patients, 60% (95% CI = 46%-74%) for black patients, and 49% (95% CI = 23%-77%) for other race/ethnicity patients. The 10-year patient survival rates were 92% (95% CI = 84%-96%), 65% (95% CI = 52%-79%), and 76% (95% CI = 54%-97%) for the white, black, and other race/ethnicity groups, respectively. In analyses adjusted for demographic, clinical, and socioeconomic characteristics, the rates of graft failure [black: hazard ratio (HR) = 2.59, 95% CI = 1.29-5.45; other: HR = 3.01, 95% CI = 1.23-7.35] and mortality (black: HR = 4.24, 95% CI = 1.54-11.69; other: HR = 3.09, 95% CI = 0.78-12.19) were higher for minority groups versus whites. In conclusion, at a large pediatric transplant center in the Southeastern United States, racial/ethnic disparities exist in pediatric and young adult LT outcomes that are not fully explained by measured SES and clinical factors.
- Discussion
- 4
- 10.1002/lt.24439
- Apr 26, 2016
- Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society
Steatosis after liver transplantation: Is it really benign?
- Research Article
- 4
- 10.1002/cpt.3288
- May 2, 2024
- Clinical pharmacology and therapeutics
On June 6, 2022, the FDA expanded the indications for mycophenolate mofetil (MMF) to include the prophylaxis of organ rejection in combination with other immunosuppressants in pediatric recipients of allogeneic heart or liver transplants aged 3 months and older. The approved oral dosing regimen for these patients was a starting dose of 600 mg/m2 with titration up to a maximum of 900 mg/m2 twice daily. Data to support efficacy in pediatric patients were derived from established pharmacokinetic (PK) relationships across approved populations, a PK study in pediatric liver transplant recipients, and information from the Scientific Registry of Transplant Recipients database. Information supporting safety was based on comparing mycophenolic acid (MPA) exposure with that in pediatric kidney transplant recipients, the published literature, and post-marketing safety reports. Efficacy in pediatric patients was established based on extrapolation of efficacy from studies in adult liver, adult heart, and pediatric kidney transplant populations, and similarity in MPA exposure between pediatric and adult patients. Review of the data supported an oral dosing regimen for pediatric heart transplant and liver transplant recipients consisting of a starting dose of 600 mg/m2 up to a maximum of 900 mg/m2 b.i.d. A dosage range for MMF is recommended recognizing that the MMF dose may be modified in clinical practice for myriad factors. The dosage recommendations in the labeling for pediatric liver and pediatric heart transplant patients are intended to permit individualized dosing based on clinical assessment of these factors.
- Ask R Discovery
- Chat PDF
AI summaries and top papers from 250M+ research sources.
