Transient hyperphosphatasemia after pediatric liver transplantation

BACKGROUND: Transient hyperphosphatasemia of infancy and early childhood is characterized by transiently increased serum activity of alkaline phosphatase (ALP), predominantly its bone or liver isoform, in children under 5 years of age. There is little information on the rate of transient hyperphosphatasemia in pediatric liver transplant recipients. METHODS: Patients who underwent liver transplantation at Ege University Organ Transplantation and Research Center, Izmir, Tureky, between January 1998 and January 2005, were included in the study. A total of 70 paediatric liver recipients' medical records were analyzed retrospectively. RESULTS: Transient isolated hyperphosphatasemia was observed in two of 70 patients and the rate of transient hyperphosphatasemia was estimated to be 2.8% in pediatric liver transplant recipient. Diarrheal episode was noted prior to the peak ALP activity in both cases. In one case the causative agent was not found, whereas in the other case Rotavirus was detected in a stool specimen. ALP activity normalized at 4 months and 18 days in the first and second cases, respectively. They continue follow up at the outpatient clinics with stable graft function. CONCLUSION: It is important to know that very high ALP levels can be seen without underlying significant pathology and the benign nature of the condition to avoid unnecessary investigations.     

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.     

Thrombotic events after pediatric liver transplantation

Ooi CY, Brandão LR, Zolpys L, De Angelis M, Drew W, Jones N, Ling SC, Fecteau A, Ng VL. Thrombotic events after pediatric liver transplantation.
Pediatr Transplantation 2010: 14:476–482. © 2009 John Wiley & Sons A/S. Abstract: TE may contribute to morbidity and mortality after LT. The objectives were to determine the incidence of early TE post‐pediatric LT and compare differences between children with and without TE. A retrospective review of 88 transplanted children (January 2002–October 2007) was performed to determine the incidence of Doppler‐confirmed DVT and ATE in the first month post‐LT. Fourteen (16%) patients developed TE: DVT in seven (8%) and ATE in seven (8%) patients. Six of 88 (6.8%) developed symptomatic CVL‐related DVT. Median (range) time post‐LT to DVT and ATE were 7 (4–18) and 8 (1–31) days, respectively. There was no significant difference in age/body weight at LT between patients with or without DVT and ATE. There was no significant difference between patients with or without HAT in age and weight at LT, cold ischemic time, duration of surgery, hematocrit levels, whole‐organ graft type, intraoperative FFP, high‐risk CMV status, or early acute cellular rejection. In conclusion, the incidence of early TE post‐pediatric LT was 16%, including DVT in 8%. Prospective studies are necessary to evaluate the role of prophylactic anticoagulation and potential modifiable risk factors post‐pediatric LT.     

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.     

Graft fibrosis in patients with biliary atresia after pediatric living-related liver transplantation

Although an LDLT can successfully treat biliary atresia (BA), some patients develop liver fibrosis or inflammation. To study the incidence and risk factors associated with these complications, we performed serial protocol biopsies. Twenty-four patients with BA who received a pediatric LDLT underwent protocol biopsies. All patients received standard tacrolimus-based immunosuppression and steroids. The last available biopsies were assessed. The mean age at the time of transplant was 4.8yr and the follow-up period ranged from 1.2 to 12.3yr. The GRWR ranged from 0.8% to 4.5%. The mean time from transplantation to the latest biopsy was 4.7yr. No complications occurred with the biopsy protocol. The last available biopsies for 13 (54%) and 4 (17%) patients indicated grade 1 and grade 2 portal fibrosis, respectively, and 14 patients (54%) had inflammation. No ductopenia was detected. A younger age at LDLT was significantly correlated with graft fibrosis (p=0.036). These results indicate that biopsy-proven fibrosis can be detected in patients with BA after LDLT, even in the context of normal liver function blood tests. Therefore, a serial biopsy is a safe and effective follow-up procedure for pediatric LDLT.     

Factors predicting persistent thrombocytopenia after living donor liver transplantation in pediatric patients

Thrombocytopenia is common after LT for pediatric end-stage liver diseases. Seventy-six pediatric patients (≤15 yr old) who underwent LDLT were evaluated for the incidence and predictive factors of post-transplant thrombocytopenia (PLT <100, 000/mm(3) ). The prevalence of thrombocytopenia at two wk and at 12 months post-transplant was 22/76 (28.9%) and 11/62 (17.7%), respectively. Thrombocytopenia at two wk after LDLT was significantly associated with age at transplant, preoperative PLT, GRWR, acute rejection, and CMV infection in univariate analysis. Moreover, preoperative PLT, GRWR, and acute rejection had a strong correlation in multivariate analysis. Thrombocytopenia at 12 months after LDLT was associated only with preoperative PLT. We also demonstrated that vascular complications caused thrombocytopenia and that successful treatment recovered the PLT. These results showed that, in addition to considering the preoperative PLT, post-operative monitoring of platelets is very helpful for the early detection of adverse events related to the graft liver in pediatric liver transplant patients.     

Cognitive and emotional outcome after pediatric liver transplantation

The aim of the study was to evaluate the cognitive and emotional development after pediatric liver transplantation. A total of 21 patients, aged 4-16.9 yr (median 9.6 yr) were tested 1-9 yr (median 4.2 yr) after the transplantation. The pretransplant diagnoses included biliary atresia (eight patients), various metabolic diseases (n = 6), acute liver failure (n = 3), and miscellaneous (n = 4). The cognitive functions were tested with Wechsler preschool and primary scale of intelligence (WPPSI)-R or Wechsler intelligence scale for children (WISC)-III according to age. The Piers-Harris self-concept scale and the evaluation of human figure drawings according to Koppitz were used to detect emotional problems. All tests in all patients were performed by the same psychologist. A significantly lower result on cognitive tests was seen when compared with the expected normal values (p < 0.01). The number of patients with results within or under the lower normal range was higher than expected. Although the mean value of the Piers-Harris self-concept scale was normal, there was a large spread within the group. Indicators of emotional problems were found in the human figure drawings of 50% of the patients. To some extent, low cognitive scores coincided with low scores on self-concept scale and indicators of emotional difficulties. We conclude that the high degree of cognitive and emotional problems after liver transplantation is an important argument for routine psychologic follow-up and support in these patients.     

Inclusion of entire pancreas in the composite liver and intestinal graft in pediatric intestinal transplantation

An entire pancreatico-duodenal complex was included in the liver and intestinal graft in eight children who received small-size grafts. This method showed several advantages compared to the traditional approach. They included reducing time for graft preparation by eliminating donor pancreas resection, no necessity of biliary reconstruction and leaving natural tissue support for blood vessels. The method was not associated with an increased risk of complications such as pancreatitis or rejection. It should be considered in pediatric liver and intestinal transplant recipients who require small-size grafts.     

Severe cytomegalovirus infection and immunosuppressive therapy in pediatric liver transplantation

Twenty-two post-orthotropic liver transplant (OLT) recipients were studied to investigate the clinical, laboratory and histopathological differences between rejection and CMV infection. The mean age at the time of transplantation was five years. Nine of 22 (41%) patients developed positive CMV, CF-IgG and IgM antibody titers and cultures for CMV following surgery, and three (group 1a) developed interstitial pneumonitis. CMV specific inclusion bodies were found in lung and liver biopsies. Two patients in group 1a were treated successfully with DHPG and decreasing immunosuppressive treatment, while the third died. Clinical presentation of rejection episodes were similar in all groups. CMV infected patients (group 1) received more transfusions of blood and blood products than the non-infected patients (group 2). Rejection episodes occurred sooner and more frequently in group 1a than in group 1b (CMV infected-asymptomatic) and group 2 (non-infected). Group 2 received fewer steroid boluses as well as azathioprine and OKT 3. A percutaneous liver biopsy with routine stains helped detect CMV when inclusion bodies were seen. We conclude that culture proven CMV infection is common post-OLT. Severe CMV infection occurred more frequently in those who had received greater doses of immunosuppressive therapy for possible graft rejection. Monitoring CMV infection following OLT is absolutely necessary. After OLT, decreasing the immunosuppressives and using antiviral agents are important in the management of CMV infection.     

Linear growth after pediatric liver transplantation.

To determine growth patterns in a large cohort of unselected children undergoing liver transplantation, the outcomes of 294 orthotopic liver transplantations performed in 221 children at The University of Chicago between October 1984 and October 1992 were retrospectively reviewed; 66% were alive at the time of this analysis. The mean age at transplantation was 4.1 +/- 5.0 years; 44% of the children were male and 16% of the transplants were from living-related donors. The mean height z score at the time of transplantation was -1.6 +/- 1.8, and 39% of children had height z scores of < -2.0 at transplantation. When children with growth retardation at the time of transplantation (height z scores of < -2. 0) were compared with children with more normal growth, there were no significant differences in gender or re-transplantation rates, although children with growth retardation at transplantation were significantly younger than those with more appropriate growth (2.8 +/- 4.1 years vs 4.7 +/- 5.1 years, P <.05). The height z score of all children with biliary atresia at the time of transplantation was -1.9 +/- 1.7 compared with -1.2 +/- 2.0 in those children with underlying diseases other than biliary atresia. Catch-up growth was seen in 37% to 47% of children at any given time point after transplantation. Children with evidence of catch-up growth (growth velocity z score >0) 2 years after transplantation were more likely to be first-time transplant recipients, had more growth retardation at the time of transplantation, and were receiving lower doses of prednisone at 2 years after transplantation. Younger children were most likely to demonstrate catch-up growth after transplantation. In summary, a large proportion of children have growth retardation at the time of liver transplantation. This growth retardation is inversely correlated with age. Before transplantation, children with biliary atresia grow less well than children with other forms of liver disease. Up to one half of children demonstrate catch-up growth after liver transplantation. Growth after transplantation is proportional to the degree of growth retardation at transplantation and inversely correlated to age at transplantation. Children with poor growth after transplantation are more likely to be receiving higher doses of corticosteroid.     

Development of autoantibodies after pediatric liver transplantation

Dn‐AIH is a long‐term complication after LT. The aim of this study was to analyze the occurrence of autoantibodies in pediatric recipients and the clinical significance. From 1992 to 2008, 96 pediatric LT for non‐autoimmune liver diseases were performed in 94 children in our institution. Serum autoantibodies were checked in 68 subjects (73.9%). A positive autoantibody was defined as titers ≥1:40 for ANA, or ≥1:20 for ASMA, anti‐LKM, and AMA. Autoantibodies were detectable in 51 of 68 patients (75.0%). There was positivity for ANA in 30 patients, ASMA in 32, and AMA in three, while anti‐LKM was all negative. Immunosuppressive treatment with CsA, more than one episode of rejection, and abnormal ALT were risk factors for the development of autoantibodies. The incidence of the development of autoantibodies was 75.0% in pediatric LT cases in this study. ASMA was the most commonly found autoantibody. Autoantibodies may not play a sentinel role for dn‐AIH after LT.     

儿童肝脏移植术后感染现状分析

自1989年首例儿童活体肝脏移植手术成功以来,肝脏移植术逐渐成为治疗儿童终末期和代谢性肝脏疾病的有效手段.近20年来,随着外科技术的日益完善及免疫抑制剂的合理应用,儿童肝脏移植术后的短期、长期存活率明显提高,但感染仍是肝脏移植术后最常见的并发症,严重影响预后.该文对儿章肝脏移植术后感染现状及合理用药作一概述.     

Pulmonary complications following liver transplantation in pediatric patients

The purpose of this study was to define the incidence and type of pulmonary complications experienced by children after orthotopic liver transplantation (OLT). The radiological records of all patients receiving OLT during a 3-yr period were reviewed to identify evidence of a pulmonary abnormality. Medical records were then reviewed to determine type, duration, therapy and outcome of pulmonary disorders. Potential risk factors for the development of persistent pleural effusions were also analyzed. One hundred and fifty-one pediatric liver transplantations were performed on 113 patients during this period. Pneumonia developed in 27 patients, including 11 proven bacterial, six presumed bacterial, six viral and four fungal cases. All three deaths related to pulmonary complications were in this group. Three patients developed mild pulmonary hemorrhages, and three developed pulmonary calcifications, which did not impair lung function. Sixteen patients developed paralysis of the right hemidiaphragm, four required diaphragm plication. Pleural effusions developed in 86 patients, 38 persisted longer than 7 days. Patients with persistent effusions were more likely to develop allograft rejection than patients with no persistent effusion (p < 0.01) by chi2 analysis. Seven patients required tracheostomy placement. Of these, four were successfully decannulated, two died from non-pulmonary complications and one is receiving home ventilator support. In conclusion, the majority of children experience at least one pulmonary complication after OLT, but mortality due to pulmonary disease is low in this population. Persistent pleural effusions may be a heralding sign of allograft rejection. Viral, bacterial and fungal pneumonia were the only pulmonary causes of death and only one patient in this series has had significant chronic lung disease.     

Oxidative stress after living related liver transplantation subsides with time in pediatric patients

Background

Oxidative stress has been suspected to influence graft survival and prognosis in pediatric recipients of living related liver transplantation (LRLT).

Purpose

We determined the oxidative status of pediatric LRLT recipients during their regular outpatient follow-up visits, and looked for a relationship between oxidative status and post-liver transplantation (post-LTx) duration.

Patients

The study included 43 patients (20 males and 23 females) between the ages of 1.6 and 25.1?years (median 10.7?years) who had undergone LRLT from 5?months to 17.5?years (median 7?years) prior to the study, between the ages of 1.2 and 14.4?years (median 3.5?years).

Methods

Serum glutamic pyruvic transaminase (GPT), glutamic oxaloacetic transaminase (GOT), gamma-glutamyl transpeptidase (??-GTP), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), direct bilirubin and choline-esterase were measured as part of the patients?? regular follow-up visits. Serum total hydroperoxide (TH) and biological antioxidative potential (BAP) were measured using the free radical analytic system which requires 20???l of serum and 10?min of processing time for each sample. Oxidative stress index (OSI) was calculated as the ratio of TH to BAP.

Results

Serum OSI correlated positively with serum levels of GOT, GPT, LDH, ALP, ??-GTP and direct bilirubin. Serum OSI, TH, LDH, ALP and GOT correlated negatively with post-LTx duration. Serum BAP correlated positively with post-LTx duration. Serum TH correlated positively with serum GOT and ??-GTP, but negatively with serum BAP.

Conclusions

(1) The OSI, which can be calculated based on data acquired through a simple outpatient procedure, can serve as an index of our patients?? laboratory results and oxidative status. (2) The LRLT recipients in our study were at risk for oxidative stress early in the post-operative period, but this risk subsided with time.     

Markers of operational immune tolerance after pediatric liver transplantation in patients under immunosuppression

A prospective identification of the estimated 20–50% of pediatric LTX recipients developing operational tolerance would be of great clinical advantage. So far markers of immune tolerance – T‐cell subpopulations or gene expression profiles – have been investigated only retrospectively in successfully weaned patients. Fifty children aged 8–265 months (median 89) were investigated 1–180 months (median 44) after LTX under ongoing immunosuppression. T‐cell subpopulations were measured during regular post‐transplant visits using FACS (Vδ1‐ vs. Vδ2‐γδ‐T cells and Tregs). A Vδ1/Vδ2‐γδ‐T‐cell ratio ≥1.42 previously reported in operational tolerance was found in 12 of 50 (24%) patients. In analogy, a Treg count ≥44 per μL was found in 35 of 50 (70%) patients and a Treg proportion ≥2.23% of CD3⁺‐T cells in 39 of 50 (78%) patients. Only 9 of 50 patients (18%) fulfilled both criteria. The parameters Vδ1/Vδ2‐γδ‐T‐cell ratio and Tregs were not significantly correlated to each other or with donor type or immunosuppression. Vδ1/Vδ2‐γδ‐T‐cell ratio was more stable in serial examinations compared with Treg analyses. The observed proportion of 18% pediatric LTX patients with potential operational tolerance is in accordance with previous reports. However, clinical experience shows that rejections may happen even after long‐time weaning of immunosuppression. This suggests that operational tolerance is a dynamic process, with uncertain prediction by Vδ1/Vδ2‐γδ‐T‐cell ratio and/or Tregs under immunosuppression.     

Vitamin D deficiency and insufficiency after pediatric liver transplantation

Vitamin D deficiency and insufficiency are increasingly recognized in the general population, including healthy children. There is also an increasing emphasis on the importance of vitamin D status following pediatric liver transplantation and specifically its relationship to metabolic bone disease and growth retardation. Vitamin D insufficiency has also been associated with multiple immunological and metabolic disorders in adults. To our knowledge, this has not been systematically evaluated in children undergoing liver transplantation to date. Between October 2004 and August 2008, serum 25‐(OH)‐vitamin D levels were measured in 199 children who had undergone liver transplantation at Birmingham Children's Hospital. Potential factors contributing to vitamin D levels were evaluated. Additionally, we evaluated a possible relationship between vitamin D levels and immunological phenomena and metabolic complications. Median 25‐(OH)‐vitamin D level was 19.5 ng/mL (range: 4.4–71.4 ng/mL). A total of 105 children (53%) had insufficient vitamin D levels and 28 children (14%) showed vitamin D deficiency. The only factors found to be associated with vitamin D deficiency were season of sample, ethnicity, and PTH levels. Vitamin D deficiency was more prevalent during the first year after transplantation. We did not find a significant relationship between vitamin D levels and graft function or any other immunological and metabolic complications. Vitamin D insufficiency and deficiency are common in children after liver transplantation, especially in winter and spring and in non‐white patients. Initial post‐transplant period and high PTH are significantly associated with vitamin D deficiency. Vitamin D status should be monitored following pediatric liver transplantation and vitamin D supplementation provided as required.