Basiliximab monotherapy following B-cell lymphoma after pediatric liver transplantation and anti-CD20 therapy

The chimeric, monoclonal antibody basiliximab inhibits the proliferation and clonal expansion of activated T cells. To date basiliximab has been used only in combination with other immunosuppressive agents for rejection prophylaxis after solid organ transplantation. An infant underwent liver transplantion (LTx) at the age of 5 months because of biliary atresia. The primary immunosuppression consisted of cyclosporine and prednisolone. As a result of a steroid resistant rejection episode on day 26 post-LTx we had to switch the initial immunosuppressive regiment to tacrolimus and steroids. Because of severe cholestasis and assumed impaired enteral resorption we were forced to administer an unusually high dosage (2 mg/kg/day) of tacrolimus. Four months after LTx an intestinal B-cell lymphoma was diagnosed when the patient suffered from a small bowel perforation. After stopping the immunosuppressive medication we started treatment with the anti-CD20 monoclonal antibody rituximab for B-cell depletion. During the 12 wk no B cells were detectable in the peripheral blood by flow cytometry. In this setting we started a monotherapy with repetitive doses of basiliximab for immunosuppression. During the following course there was no further rejection and no recurrence of the tumor. From this experience we conclude that monotherapy with basiliximab after LTx and anti-CD20 treatment for B-cell lymphoma is efficient and safe.     

Prednisone withdrawal in pediatric kidney transplant recipients on tacrolimus-based immunosuppression: four-year data

Corticosteroids have been used in renal transplant immunosuppression for over 40 yr. Despite their adverse effects, steroid therapy continues to be part of early as well as maintenance immunosuppression in most pediatric renal transplant centers. The association of steroids with growth retardation, weight gain, and acne may be particularly distressing during the critical years of adolescence and young adulthood, increasing the risk of medication non-adherence. This study reviews the outcomes of pediatric renal transplant patients treated with low-dose tacrolimus, mycophenolate mofetil, or azathioprine, and planned prednisone withdrawal. Thirty-seven pediatric renal transplant recipients were withdrawn from steroids. The mean follow-up after steroid withdrawal was 42+/-19 months. Graft and patient survival were 100%. The mean serum creatinine levels and calculated creatinine clearances remained stable throughout the period of observation. The mean creatinine clearance was 96+/-24 mL/min/1.73 m2 at steroid withdrawal and 93+/-20 mL/min/1.73 m2 at the latest follow-up. Five patients restarted prednisone; in four (11%) it was for suspected or confirmed acute rejection. Improvements were observed in serum lipid profiles, blood pressure, and body mass index. Most patients experienced catchup or stable growth after prednisone withdrawal. Four patients developed viral infections; all were successfully treated. The potential benefits of steroid withdrawal in pediatric renal transplantation are supported by our results.     

Growth in children following liver transplantation

Although liver transplantation (OLT) has become standard therapy for end-stage liver disease in children, growth after OLT remains an area of concern. We reviewed our experience with growth after OLT at the Hospital for Sick Children in 83 patients who survived at least 1 yr post-transplant. Our aims were to describe the success rate in steroid cessation in patients after transplantation, to examine the effect of transplantation on subsequent growth, to see if steroid reduction had a beneficial effect on growth, and to quantify the risk of stopping steroids on rejection. Patients below age 5 yr were weaned off steroids more easily than those over age 5: 19.2% vs. 0% (p<0.05), 65.9% vs. 50%, and 79.5% vs. 37.5% (p<0.05) at post-transplant years 1, 2, and 3, respectively. Pre-transplant, 30% of patients were below the third percentiles for height and weight. Post-transplant, there was a steady improvement in the distribution of patients above the 3rd percentile, so that by post-transplant year 6, only 5% were below the 3rd percentile. Height and height velocity percentiles were found to correlate inversely with total yearly steroid dose (mg/kg) at post-transplant years 2, 3 and 6 (p<0.05). In 60% of patients, steroids were successfully discontinued. In these patients, height and height velocity percentiles have achieved a near normal distribution with 40% and 46% of patients above the 50th percentile for height and height velocity percentiles, respectively. No grafts were lost to rejection in those off steroids, and all rejection episodes were easily reversed. We conclude that the majority of children can be weaned off steroids successfully after OLT and that growth in those children in the presence of good graft function is near normal.     

Using individual DSA titers to assess for accommodation after late humoral rejection

Management of late humoral rejection remains challenging, and DSA may persist. A case report illustrates how individual DSA titers using solid‐phase‐based assays may help to assess for accommodation. A male cystinosis patient received a cadaveric renal transplant at the age of 12 yr with a daclizumab, tacrolimus, MMF, and steroids‐based immunosuppression. After three acute rejection episodes over the first eight months, interstitial fibrosis/tubular atrophy (IF/TA) was diagnosed on biopsy, while the immunosuppression was left unchanged with a high target exposure for both tacrolimus and MPA. One yr later, AMR type III (C4d and DSA positive) was treated with daily plasmapheresis, IVIG 100 mg/kg and pulse steroids 5 mg/kg. DSA (DR 53, DQ4, and DQ 2) were not responding until the plasma volume was increased to 2.5 plasma volumes. A second rise of creatinine confirmed worse humoral rejection; daily plasma exchange was resumed, and two doses of rituximab (375 mg/m²) were given. Subsequently, all DSA dropped, but only DR53 DSA remained unchanged, whereas the DQ antibodies rebounded to very strong titers. With a follow‐up of over 120 days after recovery of the CD19 count, off all additional treatment and on identical immunosuppression with tacrolimus and MMF and prednisone, the patient's creatinine remained stable between 45 and 50 um while DQ DSA remain strong to very strong. We conclude that the patient is in a state of accommodation. DSA titers should be monitored when managing late humoral rejection.     

Rapid steroid discontinuation for pediatric renal transplantation: a single center experience

To determine the outcomes of pediatric renal transplant recipients who received immunosuppression consisting of early withdrawal of corticosteroids at a single Northern California center. Protocols using minimal steroid exposure have been recently reported in adult transplant recipients with successful results. We examined the outcomes of pediatric renal transplant recipients who were managed at our center using a protocol with very early discontinuation of steroids after renal transplantation. We retrospectively studied the medical records of all renal transplant recipients followed at the Children's Hospital at the University of California, Davis Medical Center from 01/2004 to 12/2005. All patients were less than 18 yr of age at the time of transplantation. The immunosuppressive protocol included three tapering daily doses of methylprednisolone, together with five doses of thymoglobulin followed by maintenance therapy with tacrolimus and MMF. Eight patients with equal numbers of males and females were transplanted during this time period. There were equal numbers of Caucasians, African-Americans, Hispanics, and Asians. A total of 37.5% (3/8) of the subjects received preemptive transplantation, 25% (2/8) received peritoneal, and 37.5% (3/8) received hemodialysis before transplantation. The median (range) age at transplantation was 12.3 (3.1-16.0) year with a follow-up of 1.7 (0.9-2.8) year. At one yr post-transplantation, 57% (4/7) of patients still required anti-hypertensives. Three children required erythropoietin supplementation after transplantation. The mean delta height standard deviation score at 12 months was 0.20 +/- 0.56. There were no episodes of clinical acute rejection. One patient switched from tacrolimus to sirolimus due to biopsy-proven CAN. No patient became diabetic or required hypoglycemic agents. Surveillance biopsies showed no subclinical acute rejection in any patient. Steroid-free immunosuppression is safe in children after renal transplantation. Larger number of patients and longer follow-up are required to further confirm the effectiveness and safety of immunosuppression with rapid steroid discontinuation.     

Immunosuppression in infants with short bowel syndrome undergoing isolated liver transplantation

BACKGROUND: Little data exist on immunosuppressive drug absorption in children with short bowel syndrome and intestinal failure associated liver disease (SBS-IFALD). AIM: To evaluate the absorption of immunosuppressive medications in children with SBS-IFALD undergoing isolated liver transplantation (iLTx). METHODS: A retrospective review was performed in children with SBS-IFALD undergoing LTx and comparison made with weight, age-matched children undergoing iLTX (extra-hepatic biliary atresia (EHBA) and normal intestinal length and function). RESULTS: Seven children with SBS-IFALD undergoing iLTx (median residual bowel length, 60 cm, range 40-80) were compared with 15 children undergoing LTx for EHBA. SBS-IFALD children had significantly lower trough tacrolimus levels at three months (5.8 vs. 7.9 ng/mL, p<0.05) and six months (5.0 vs. 8.0 ng/mL, p<0.05), but equivalent levels at 12 months after iLTx. The median calculated dose-normalized concentrations indicated that systemic availability of tacrolimus was comparable in two groups at 3, 6, 12 months (33.1 vs. 23.3; 42.4 vs. 36; 51 vs. 52.9) despite the differences in enteral function. The incidence of acute rejection was 1/7 (SBS-IFALD) and 10/15 (EHBA) group (p = 0.06). CONCLUSION: Children with SBS-IFALD demonstrated adequate absorption of oral tacrolimus without significant acute rejection rate after iLTx suggesting that modification of immunosuppression is not necessary.     

Results of one-year follow-up of steroid-free immunosuppression in pediatric renal transplant patients

Renal transplantation in children has traditionally required immunosuppression with multiple medications including glucocorticoids. Data collected over almost 30 yr suggest that although glucocorticoids are efficacious as part of a regimen to minimize the incidence of acute rejection episodes, their use is associated with increased risk for post-transplant hypertension, hyperlipidemia, and reduced growth rates. We desired to reduce these complications and thus used an immunosuppressive protocol including daclizumab, tacrolimus, and mycophenolate mofetil and study the efficacy of this protocol in a population with a high percentage of African-American recipients. No patient received glucocorticoids at any time post-transplant. Our results show that at 1 yr post-transplant, glomerular filtration rate, serum glucose, calcium and phosphorous metabolism, serum magnesium, and serum lipids were similar in patients receiving steroid-free and those receiving steroid-based immunosuppression. The incidence of acute rejection was similar in the two groups. Hematocrit and white blood count levels were lower 1 month after transplant in the steroid-free patients but these levels increased within several months. Systolic blood pressure was similar in the two groups, although this was achieved, in part, in the patients who received steroids by the administration of medications to lower blood pressure. Finally, tacrolimus levels were similar in the two groups, but patients receiving steroids required higher doses of tacrolimus at several time points studied during the first post-transplant year. Taken together, our data suggests that at one-year follow-up, steroid-free immunosuppression is safe, and efficacious in pediatric renal transplant recipients.     

Safety and efficacy of tacrolimus in pediatric liver recipients

Pediatric liver transplantation is now so successful that we expect more than 80% of children to survive into adolescence and adulthood. As the focus of care shifts toward long-term patient management, immunosuppressive regimens should, in addition to preventing acute and chronic rejection, promote good quality of life and be free of significant long-term side effects. Historically, the most effective immunosuppressive regimens have been based on induction with a combination of calcineurin inhibitors (cyclosporin or tacrolimus) and steroids. Usually, maintenance is monotherapy with cyclosporin or tacrolimus or dual therapy with low-dose alternate-day steroids to encourage growth. A number of studies, including long-term follow-up, have shown significantly lower incidences of rejection, hypertension, hyperlipidemia and cosmetic side effects in patients treated initially with tacrolimus compared with cyclosporin. The use of anti-interleukin-2 inhibitors as induction therapy, with low-dose tacrolimus or in combination with mycophenolate mofetil, has a key role in preventing significant renal dysfunction and reducing infection and rejection. Steroid-free immunosuppression is also proving to be an effective option for the management of pediatric liver recipients. The main challenges now facing pediatricians include ensuring long-term quality of life, optimizing immunosuppression while preventing associated adverse events, and managing a smooth transition from childhood to adolescence and adulthood.     

The optimal immunosuppressive protocol for the portal vein infusion of PGE1 and methylprednisolone in pediatric liver transplantation for fulminant hepatic failure of unknown etiology

The outcome of LTx in pediatric patients with FHF of unknown etiology remains inferior to that of LTx in pediatric patients with cholestatic diseases. A higher incidence of steroid‐resistant severe rejection has been increasingly recognized among the responsible factors. We assessed the efficacy of the administration of steroids and PGE1 via PVI in the management of LTx for FHF in pediatric patients. In our early cohort (1995–2007), seven patients who underwent LTx for FHF of unknown etiology were treated with conventional immunosuppressive therapy (calcineurin inhibitor and a steroid). Seven of eight grafts (one patient underwent re‐LTx) sustained CV and/or CPV associated with ACR, and four patients died of a graft failure or infectious complications that were associated with the treatment for rejection. Of note, the pathological incidence of CV/CPV was significantly higher in recipients with FHF of unknown etiology than in recipients with biliary cholestatic disease during the same study period (87.5% vs. 13.7%, p < 0.00001). From 2008, three patients underwent LTx for cryptogenic FHF with PVI and conventional IS. PVI was well tolerated, and no relevant severe complications were observed. More strikingly, the patients who received PVI overcame biopsy‐proven immunological events and are all currently doing well with excellent graft function after more than five yr. We conclude that PVI is technically safe and effective for preventing severe rejection in pediatric patients who undergo LTx for FHF of unknown etiology and that it does not increase the risk of fatal infectious complications.     

Long‐term outcomes in pediatric liver recipients: Comparison between cyclosporin A and tacrolimus

In recent years, tacrolimus (FK506, TAC) has been increasingly utilized in liver transplantation. However, long-term risks and benefits as compared with conventional cyclosporin A (CsA) have not been fully elucidated. This retrospective study examined the potential outcome differences between TAC- and CsA-based immunosuppressive therapy in pediatric liver transplant recipients. From March 1988 to December 1996, 218 children (aged 0.1-17 yr) underwent 238 orthotopic liver transplantations; 58.7% (128/218) were under 2 yr of age at time of transplant. Initially, the maintenance immunosuppressive regimen consisted of CsA and prednisone, with antilymphocytic preparations (MALG, ATGAM, and OKT3) as induction therapy. Subsequently, TAC was used first as rescue therapy for steroid refractory rejection in CsA patients and then as maintenance immunosuppression. Fifty-seven out of the 147 CsA patients were converted to TAC for various reasons while 71 patients were placed on TAC as primary maintenance immunosuppression. 62.6 per cent (92/147) of liver recipients on CsA experienced at least one biopsy-proven acute rejection episode as compared to 50.7% (36/71) for TAC patients (p = 0.09); likewise, 34% (50/147) of CsA patients had more than one episode of rejection vs. 18.3% (13/71) for patients on TAC (p < 0.02). Rejection was the reason for conversion from CsA to TAC in 29 of 57 patients. Conversely, 19.0% (28/147) of CsA patients had to be switched to TAC for reasons not related to rejection (i.e. side-effects). The overall incidence of histologically proven chronic rejection was 7.8% (17/218). 10.9 per cent (16/147) of the children who were on CsA initially developed chronic rejection, which was significantly higher compared with one of 71 TAC recipients (p < 0.02). Of these 16 CsA patients with chronic rejection, 50.0% (8/16) underwent retransplantation for graft failure (mean interval from time of diagnosis of chronic rejection to re-transplant, 4.0 months; range 1-8 months), whereas the TAC patient has remained clinically stable with normal liver function tests after 23 months of follow-up. One year after liver transplantation, 72.8% (107/147) of CsA patients were still on steroids (mean dosage 0.20 mg/kg/d), as compared to 42.3% (30/71) of the TAC patients (mean dosage 0.14 mg/kg/d). The incidence of post-transplant lymphoproliferative disorder (PTLD) in Epstein-Barr virus (EBV)-infected patients was 2.2% (2/90), 7.0% (5/71) and 12.3% (7/57) for CsA, primary and TAC-converted groups, respectively. The overall incidence of PTLD was 6.9% (15/218). In summary, pediatric liver transplant recipients treated with TAC as primary maintenance immunosuppressive medication experienced significantly fewer episodes of rejection; especially chronic rejection, which lead to graft loss. However, the trade-off is a potential increased incidence of EBV-related PTLD in these patients.     

儿童肾移植临床免疫抑制用药探讨

目的　探讨儿童肾移植免疫抑制治疗特点。方法　回顾性分析 31例儿童肾移植患者(男 18例,女 13例)的临床资料。根据起始免疫抑制方案不同,分为 3组:A组(环孢素A+硫唑嘌呤+泼尼松)7例;B组(环孢素A+霉酚酸酯 +泼尼松)17例;C组 (他克莫司 +霉酚酸酯 +泼尼松)7例。统计 3组免疫抑制药物调整及维持剂量、移植肾功能变化和术后并发症。结果　1年人 /肾存活率为100% /96.8%,3年人 /肾生存率为94.4% /88.9%。三组各观察点肌酐实测值差异无显著性意义 (P<0.05)。他克莫司组药物副作用小且能保持良好的肾功能。泼尼松调整幅度大、维持量小,与其他组差异有显著性意义(P<0.01)。结论　肾移植是儿童终末期肾病的有效治疗措施。遵循儿童个体差异的免疫抑制治疗是移植后预防排斥的重点。他克莫司、霉酚酸酯、泼尼松三联抗排斥治疗是儿童肾移植理想的免疫抑制治疗方案。     

Mycophenolate mofetil in pediatric heart transplant recipients: a single-center experience

Mycophenolate mofetil (MMF) is emerging as an effective agent for the treatment of both established rejection and primary rejection prophylaxis in solid-organ transplantation (Tx). However, little data is available on the use of MMF in the pediatric population. We therefore report on our experience with MMF in 21 pediatric heart transplant recipients. Data were obtained by retrospective chart review. Median age at time of review was 12.3 yr (range 11 months to 16.9 yr). Median age at Tx was 10.7 yr (range 55 days to 16.7 yr). MMF was started at a median of 4.3 months after Tx (range 1 day to 4.5 yr). At the time of MMF institution, all patients were concurrently on prednisone and azathioprine; 20 of these patients were also undergoing treatment with tacrolimus (median dose 0.18 mg/kg, range 0.03-0.64 mg/kg) and one with cyclo-sporin A (10 mg/kg). Azathioprine was discontinued at the time of commencing MMF. The average MMF dose was 40 +/- 14 mg/kg. The rationale for switching to MMF included rejection (International Society for Heart and Lung Transplantation [ISHLT] 3A/B), 66%; inability to wean steroids, 14%; ABO blood group donor-recipient mismatch, 10%; coronary artery disease (CAD), 5%; and side-effects of immuno-suppression, 5%. Of the patients switched for rejection, 93% demonstrated resolved or improving rejection. Both ABO donor-recipient mismatch patients were started on tacrolimus/MMF as primary therapy and had no significant episodes of rejection. Two patients had rejection classified as unchanged (one with CAD, one treated with addition of sirolimus prior to improvement). Corticosteroids were successfully discontinued in 28% of patients, and 20% are currently on a reduced dose. Fourteen per cent developed significant rejection while attempting to reduce the steroid dose. Steroid reduction has not yet been attempted in 38% of patients. The following side-effects were reported in 38% of the patients: diarrhea, 10%; gastrointestinal discomfort, 20%; and leukopenia, 20%. Dose reduction or temporary discontinuation was required in 63% of the patients who experienced side-effects (24% of the total number of patients). Opportunistic infections developed in 10% (cryptococcus, cytomegalovirus). Hence, MMF appears to be effective for treatment of rejection in the pediatric heart transplant population and has an acceptable side-effect profile. In addition, it may have a role in primary rejection prophylaxis and may facilitate a reduced steroid dosage or a steroid-free immunosuppression regimen.     

Prope tolerance after pediatric liver transplantation

pT, under mono‐ and infratherapeutic calcineurin inhibition, may constitute an optimal condition combining graft acceptance with low IS load and minimal IS‐related toxicity. We reviewed 171 pediatric (<15.0 yr) survivors beyond one yr after LT, transplanted between April 1999 and June 2007 under tacrolimus‐based regimens (median follow‐up post‐LT: 6.0 yr, range: 0.8–9.5 yr). Their current status regarding IS therapy was analyzed and correlated with initial immunoprophylaxis. pT was defined as tacrolimus monotherapy, with mean trough blood levels <4 ng/mL during the preceding year of follow‐up, combined with normal liver function tests. The 66 children transplanted before April 2001 received a standard tacrolimus–steroid regimen. Beyond April 2001, 105 patients received steroid‐free tacrolimus–basiliximab or tacrolimus–daclizumab immunoprophylaxis. In the latter group, 43 (41%) never experienced any acute rejection episode and never received steroids. In the long term, a total of 79 recipients (47%) developed pT (n = 73) or IS‐free operational tolerance (n = 6), 27 of them belonging to the 43 steroid‐free patients (63%). In contrast, only 52/128 (41%) children treated with steroids subsequently developed prope/operational tolerance (p = 0.012). Steroid‐free tacrolimus‐based IS seems to promote long‐term graft acceptance under minimal/no IS. These results constitute the first evidence that minimization of IS, including steroid avoidance, might be tolerogenic in the long term after pediatric LT.     

Can pediatric steroid‐free renal transplantation improve growth and metabolic complications?

We analyzed the effects of a steroid avoidance protocol in pediatric renal transplant recipients on calculated CrCl (Schwartz), CMV infection, cholesterol, height Z scores, weight Z scores, and BMI Z scores in a case control trial with contemporaneous controls. From 1999 to 2004, 19 pediatric patients (age 1-20 yr) received transplants without steroids using immunosuppression with tacrolimus, mycophenolate mofetil, and daclizumab. Control patients (n = 30) were matched for length of follow-up (minimum one yr), donor type age, type of immunosuppression, sex, date of transplant, and original disease, and CMV status. Graft survival at one year was 100% in both groups. Mean CrCl of steroid-free vs. control patients were not different at 1 year post-transplant. CMV disease was more prevalent in steroid-treated control group (seven of 30 patients) vs. the steroid free control group (zero of 19). Height delta Z scores at one year were NOT different between groups. Weight and BMI delta Z scores were significantly higher in the control group. Cholesterol levels at one year post-transplant were different in the two groups but NOT ABNORMALLY elevated in either group. At one yr post-transplant, steroid-free immunosuppression with tacrolimus, mycophenolate mofetil and daclizumab provides outcomes that are equivalent or superior to those in contemporaneous control patients receiving steroids.     

Tacrolimus: the good, the bad, and the ugly

The aim of this study was to evaluate the efficacy and side-effects of tacrolimus in pediatric transplant patients previously receiving cyclosporin A (CsA). This study was a retrospective chart review strengthened by a concomitant patient interview. Eleven pediatric cardiac or renal transplant patients, who had been converted from CsA to tacrolimus from October 1995 to January 1999 at The Cleveland Clinic Foundation, were included; there were six renal and five cardiac transplant patients. Each chart was reviewed to assess transplanted organ function pre- and post-conversion. For the six renal transplant patients, creatinine levels and biopsy findings were evaluated. For the five cardiac transplant patients, cardiac catheterization and routine biopsy data were analyzed likewise. Epstein Barr virus (EBV) status was also evaluated in each patient. In addition, each parent or patient was interviewed to ascertain dates of transplant, current medications, and side-effects. The patients' ages ranged from 6 to 20 yr (mean age 14.6 yr). All patients had been converted to tacrolimus. Eight patients were converted for treatment of refractory rejection, two were converted because of CsA-associated side-effects, and one patient was converted empirically for a history of multiple previous transplant rejections. Seven out of eight patients who received tacrolimus for rejection therapy improved. One patient had complete resolution of gingival hyperplasia. Another patient who previously developed hemolytic uremic syndrome on CsA had no further evidence of hemolysis. Four patients were weaned off steroid therapy. Despite conversion, two renal transplant patients progressed to chronic rejection. Five patients exhibited no side-effects. Side-effects experienced included transient hyperglycemia in conjunction with steroid use, headaches, and tremors that subsided rapidly. Four of 11 patients developed post-transplant lymphoproliferative disease (PTLD). Fortunately, reducing the dose of tacrolimus and/or surgical resection of the mass (if present), eradicated the disease. In conclusion, conversion therapy successfully provides an alternate treatment for acute rejection. It also enabled some patients to discontinue steroid therapy, maximizing growth potential. PTLD is a severe, potentially life-threatening complication that needs to be recognized and monitored closely. In conclusion, tacrolimus has been shown to be a very effective agent for the treatment of refractory organ rejection, but must be used cautiously.     

Sirolimus in pediatric gastrointestinal transplantation: the use of sirolimus for pediatric transplant patients with tacrolimus-related cardiomyopathy

Hypertrophic obstructive cardiomyopathy (HOCM) associated with the use of tacrolimus is a rare complication of liver and intestinal transplantation seen almost exclusively among pediatric patients. Reduction of tacrolimus dosage or conversion to cyclosporin A (CsA) has been used as an effective treatment in reviewed cases. We present three pediatric transplant recipients who developed hypertrophic obstructive cardiomyopathy while under tacrolimus immunosuppression and were treated with conversion to sirolimus (Rapamycin). The patients (ages 6 yr, 12 yr and 11 months) were transplant recipients (liver, n = 2; liver and intestine, n = 1) who developed significant cardiomyopathy 15 and 96 months post-transplant. One patient died of post-transplant lymphoproliferative disorder 21 days after starting sirolimus. One patient had received two liver transplants and had been on CsA for 12 yr before conversion to tacrolimus at 60 months post-transplant for acute and chronic rejection. The surviving patients were receiving mycophenolate mofetil, tacrolimus and steroids at the time of diagnosis. Dose reduction of tacrolimus and treatment with beta blockers failed to alleviate the hemodynamic changes. The patients were converted to sirolimus 1.6, 37 and 148 months post-transplant and maintained a whole-blood trough level of 15-20 ng/mL 21 days after starting sirolimus. Repeat echocardiograms in the surviving patients showed improvement in cardiomyopathy. One patient had one rejection episode (intestinal biopsy, mild acute cellular rejection) after starting sirolimus that responded to a transient increase in steroids. The early demise of the third patient after sirolimus conversion prevented an adequate assessment of cardiomyopathy. Conversion to sirolimus was associated with a reduction in the cardiomyopathy of the two surviving patients while still providing effective immunosuppression. To our knowledge this observation has not been previously reported.     

Hypogammaglobulinemia in pediatric liver transplant recipients

Hypogammaglobulinemia has been reported after solid organ transplantation in adults, however immunoglobulin replacement [intravenous immunoglobulins (IVIG)] is only necessary in a minority of affected patients. We here present three pediatric patients with severe post-transplant hypogammaglobulinemia following liver transplantation (LTx) receiving a cyclosporine-based standard immunosuppression. Patient 1 was transplanted at the age of 10 months for biliary atresia. Eight weeks post-Ltx the serum IgG was 1.7 g/L. Patient 2 was transplanted at the age of 12 yr for acute liver failure. Four weeks post-Ltx the IgG dropped to 2.6 g/L. Patient 3 was transplanted at the age of 4 months for biliary atresia. Ten weeks post-Ltx severe hypogammaglobulinemia (IgG < 1.48 g/L) was diagnosed during a severe infectious complication. Patients 1 and 3 received a steroid bolus therapy for acute graft rejection. All patients had normal IgG concentrations prior to Ltx and lymphocyte subsets were post-operatively in the normal range. There was no extensive loss of protein by ascites. IGIV were replaced in the three patients monthly without further complications. In two of the patients (1 and 3) IVIG therapy was discontinued 8 and 10 months after Ltx when the immunosuppression has been reduced and serum IgG concentrations were found in the normal range without further immunoglobulin replacement. Severe hypogammaglobulinemia is a rare phenomenon following pediatric LTx and seems to be mainly caused by immunosuppressive drugs, however, the exact underlying mechanisms are unclear. A screening for hypogammaglobulinemia is useful after pediatric LTx, especially in patients with an intensified immunosuppression. Moreover, further immunologic research in affected patients is necessary.     

Use of basiliximab in pediatric liver transplantation for Langerhans cell histiocytosis

This report describes a 16-month-old girl with multi-system Langerhans cell histiocytosis (LCH), who developed end-stage liver disease despite intensive chemotherapy. She underwent a liver transplant at 28 months of age while receiving maintenance chemotherapy for bony lesions. In view of previous reports of a high incidence of acute cellular rejection and post-transplant lymphoproliferative disease (PTLD) in children transplanted for LCH, basiliximab was added to the post-transplant immunosuppression regime of tacrolimus and prednisolone. Sixteen months post-transplant, she has had no episodes of acute rejection or PTLD and her LCH has remained in remission. Current literature regarding liver transplantation (LTx) for LCH and the use of basiliximab in pediatric LTx is reviewed.     

Long-term evaluation of cyclosporine and tacrolimus based immunosuppression in pediatric liver transplantation

Both calcineurin inhibitors (CNIs), cyclosporine and tacrolimus, are widely used in pediatric liver transplant recipients and currently data are limited with regards to long-term results using the one drug or the other in comparable low doses. We conducted the present study to assess the advantages and disadvantages of both drugs in children at least five yr post-liver transplantation. A total of 129 children were enrolled in the study. Thirty-eight of the children were switched to tacrolimus monotherapy for different reasons [steroid resistant graft rejection (n = 15), chronic rejection (n = 5), severe acute rejection (n = 4), repetitive acute graft rejection (n = 5), dysfunction of the transplant (n = 3), insufficient CsA metabolism (n = 3), hypertrichosis (n = 2), and CsA toxicity (n = 1)], four patients had primary tacrolimus therapy, and 87 patients are receiving cyclosporine. Mean trough levels were 5.3 +/- 2.3 ng/mL (tacrolimus) and 73.6 +/- 44.5 micro/L (cyclosporine), respectively at least five yr post-orthotopic liver transplantation (OLT). There was no significant difference in the calculated glomerular filtration rate between children on cyclosporine and tacrolimus (142.7 + 39.5 mL/min/1.73 m(2) vs. 151.1 +/- 44.1 mL/min/1.73 m(2)). The incidence of arterial hypertension was 7.1% vs. 9.2%, that of hepatotoxicity was 0% vs. 2.3%. Cosmetic changes were found in more than one-third of the patients on cyclosporine and in 4.8% of the patients receiving tacrolimus. Quality of life was excellent in both groups (self assessment). The impact of CNIs on chronic graft dysfunction cannot be assessed by our present study. We conclude from the results that cyclosporine and tacrolimus are both excellent drugs for maintenance immunosuppression in the long-term course following pediatric liver transplantation. However, this retrospective analysis is limited by the bias between children on CsA as compared with patients receiving tacrolimus. A prospective randomized controlled trial is needed in order to assess which CNI is the best for children following OLT.     

Calcineurin inhibitor minimization in pediatric liver allograft recipients

Abstract:  The use of CNI in pediatric LTx has dramatically improved the outcome for children with end-stage liver disease by significantly reducing the rate of acute and chronic rejection. Long-term concerns about CNI-induced nephrotoxicity and other adverse effects remain an issue, particularly as the emphasis moves from short-term survival to long-term quality of life. This review summarizes lessons learnt from pediatric and adult solid organ transplantation in minimizing CNI use in immunosuppression protocols in children following LTx. There are three models for CNI minimization: dose reduction, withdrawal or avoidance, supplemented by the use of IL-2 receptor blocking antibodies in the peri-transplant period, and early transition to alternate drugs such as MMF or SRL. Prospective studies evaluating reduction or withdrawal protocols in adult and pediatric LTx indicate that rejection rates are comparable with traditional CNI-based immunosuppression and that two and five yr patient and graft survival are similar, with recovery in renal function. There are few studies evaluating complete avoidance of CNI, apart from that in renal transplantation, although the benefits of long-term reduction in cardiovascular, metabolic, and possibly neoplastic side effects may justify this approach. It is not clear yet how CNI minimization will affect the development of tolerance but experimental and preliminary clinical studies indicate that CNI and steroid avoidance or minimization in the peri-operative period may favor the development of long-term graft tolerance. In summary, CNI minimization may be safe and effective in the short term but large-scale pediatric randomized studies are required to evaluate the long-term efficacy of these regimes in the development of chronic rejection, PTLD, and graft tolerance.