Cross-cutting view of current challenges in paediatric solid organ and haematopoietic stem cell transplantation in Europe: the European Reference Network TransplantChild.

The low prevalence of European paediatric transplanted patients and scarcity of resources and expertise led to the need for a multidisciplinary network able to improve the quality of life of paediatric patients and families requiring a solid organ or haematopoietic stem cell transplantation. The European Reference Network (ERN) TransplantChild is one of the 24 ERNs established in a European legal framework to improve the care of patients with rare diseases. ERN TransplantChild is the only ERN focused on both solid organ and haematopoietic stem cell paediatric transplantation, based on the understanding of paediatric transplantation as a complex and highly specialised process where specific complications appear regardless the organ involved, thus linking the skills and knowledge of different organ disciplines. Gathering European centres of expertise in paediatric transplantation will give access to a correct and timely diagnosis, share expertise and knowledge and collect a critical mass of patients and data that increases the speed and value of clinical research outcomes. Therefore, the ERN TransplantChild aims for a paediatric Pan-European, Pan-transplant approach.

Liver transplantation in children with hepatocellular carcinoma. Do Milan criteria apply to pediatric patients?

HCC constitutes 25-30% of primary malignant liver tumors in children. Conventional surgical excision is not possible in more than 50% of patients. LTx has recently become an important therapeutic option for adults and children with primary liver tumors. The aim of this study was a retrospective analysis of the clinical and pathological data of children with HCC treated with LTx in relation to Milan criteria assessed at diagnosis and then immediately before transplantation, in comparison with a group of patients treated conventionally. Between 1990 and 2007 we have treated 21 children diagnosed with HCC. Patients were divided into two groups: group I, 10 children treated conventionally and group II, 11 children treated with LTx regardless of previous therapy. The outcome of our patients treated conventionally with resection and chemotherapy is very poor--the disease-free survival rate is 30%. In contrast, despite that only 3 children having fulfilled adult Milan criteria, early clinical results of LTx are much superior. Total hepatectomy followed by LTx is the main treatment option for the majority of children with HCC. Decisions on the type of surgical treatment is made individually, but very early in the course of treatment.

Effects of prophylactic use of taurolidine-citrate lock on the number of catheter-related infections in children under 2 years of age undergoing surgery.

Central venous access poses a risk for the development of catheter-related infections (CRIs). The aim of this study was to evaluate prophylactic use of taurolidine-citrate (T-C) solution on the number of CRIs. Ninety-seven catheters, used in 86 children, were divided at random into two groups: Group T(-) (N=49) underwent standard aseptic procedures, and Group T(+) (N=48) received additional filling of the lines with T-C solution during intervals in cycles of parenteral nutrition or drug supply. Sixteen CRIs occurred in Group T(-) and one CRI occurred in Group T(+); this difference was significant (P<0.05). Use of T-C appears to be a safe and effective method for the prevention of CRIs.

Combined Liver-Kidney Transplantation in Children: Single-Center Experiences and Long-Term Results.

Combined liver-kidney transplantation (CLKT) is a rare procedure in pediatric patients in which liver and kidney from 1 donor are transplanted to a recipient during a single operation. The aim of our study was to analyze indications and results of CLKT in children. MATERIALS AND METHODS: Between 1990 and 2017 we performed 722 liver transplantations in children; we performed 920 kidney transplantations in children since 1984. Among them, 25 received CLKT. Primary diagnosis was fibro-polycystic liver and kidney disease in 17 patients, primary hyperoxaluria type 1 in 6 patients, and atypical hemolytic uremic syndrome-related renal failure in 2 children. Age of patients at CLKT was 3 to 23 years (median 16 years) and body mass was 11 to 55 kg (median 35.5kg). All patients received whole liver graft. Kidney graft was transplanted after liver reperfusion before biliary anastomosis. Cold ischemia time was 5.5 to 13.3 hours (median 9.4 hours) for liver transplants and 7.3 to 15 hours (median 10.4 hours) for kidney transplants. In 8 patients X-match was positive. We analyzed posttransplant (Tx) course and late results in our group of pediatric recipients of combined grafts. RESULTS: Tx follow-up ranged from 1.5 to 17 years (median 4.5 years). Two patients died: 1 patient with oxalosis lost renal graft and died 2.6 years after Tx due to complications of long-term dialysis, and 1 died due to massive bleeding in early postoperative period. Twelve patients were transferred under the care of adult transplantation centers. Six patients were dialyzed after CLKT due to acute tubular necrosis, and time of kidney function recovery was 10 to 27 days in these patients. In 1 patient with aHUS, renal function did not recover. In children with oxalosis, hemodialysis was performed for 1 month after Tx as a standard, with the aim to remove accumulated oxalate. Primary immunosuppression consisted of daclizumab or basiliximab, tacrolimus, mycophenolate mofetil, and steroids. Acute rejection occurred in 4 liver and 3 kidney grafts. One patient required liver retransplantation due to hepatitis C virus recurrence and 2 patients required kidney retransplantation. Two patients required dialysis. CONCLUSIONS: CLKT in children results in low rate of rejection and high rate of patient and graft survival.

Good and bad prognosis of alpha-1-antitrypsin deficiency in children: when to list for liver transplantation.

Alpha1-antitrypsin deficiency (alpha1-ATD) is a genetic disorder that may predispose to chronic liver disease. The clinical manifestations and prognosis of this disorder are variable. The aim of the study was to evaluate the clinical presentation and liver tests in two groups of children with alpha1-ATD: those with a good prognosis who survived long term with their native liver, and those with a bad one, requiring liver transplantation (OLT) or dying before OLT. We studied 59 children homozygous for alpha1-ATD admitted to our hospital with cholestasis or chronic hepatitis since infancy. Patients without liver transplantation were regarded to be the good prognosis group I (n=45). In contrast the 11 children who required liver transplantation and the three who died before OLT were the bad prognosis cohort (Group II, n=14). We analyzed the laboratory parameters of cholestasis, hepatitis, and liver insufficiency in both groups. In the group with a good prognosis, eight children still suffered from cholestasis at the ages of 9 to 14 years while nine had hepatitis at the ages of 9 to 14 years. We observed a temporarily increased international normalized ratio (1.2 to 1.5) in eight subjects at the ages of 1 month to 17 years, and slight hypoalbuminemia (30 to 35 mg/dL) in nine children at the ages of 1 month to 10 years. OLT was performed in 11 children at the ages of 10 to 17 years. Our center's experience suggested that in the PiZZ patients with portal hypertension, esophageal varices, or deterioration of hepatic function, liver transplantation should not be delayed.

Prevention of de novo hepatitis B virus infection by vaccination and high hepatitis B surface antibodies level in children receiving hepatitis B virus core antibody-positive living related donor liver: case reports.

Transmission of hepatitis B virus (HBV) infection from donors negative for hepatitis B surface antigen (HBsAg) but positive for antibody to hepatitis B core antigen (anti-HBc) have been reported. The aim of our study was to evaluate the outcomes of recipients who received liver grafts from living related donors with serological evidence of previous exposure to hepatitis B virus (HBsAg-negative/anti-HBc-positive) after recipient vaccination against HBV before and after liver transplantation.

Organ donation in Poland 2006.

Organ transplantation program has been slowly developing over last 30 years. The number of DD (deceased donors) stabilized on the level of approximately 13/million of population. Multiorgan donation has been 45%, due to some problems with donor management. Polish Transplant Coordinating Center POLTRANSPLANT which is responsible for organization of procurement, organ allocation and providing several registries (registry of objections, registry of transplantation, waiting lists of potential organ recipients etc). National data on organ donation and transplantation are each year submitted to the Ministry of Health and the National Transplantation Council which is the Advisory Committee to the Minister.

Analysis of neurological complications in children transplanted due to fulminant liver failure.

Treatment of patients with fulminant liver failure is a challenge of contemporary medicine. Liver transplantation, in this group, is presently the only reasonable alternative, but in many patients the disastrous condition of the patient results in serious life-threatening complications, including neurological sequelae, which may influence the quality of life after transplantation, and in some cases even cause death. From 1990 to 2004, we performed 241 liver transplantations in children, including 20 transplanted due to fulminant liver failure (8.2%). Serious neurological complications followed liver transplantation in five cases (20%), three of which were fatal. The analysis revealed that the duration of pretransplant coma (grade III or IV) strongly correlated with the incidence of neurological complications (P < .05). Also a suboptimal quality of the donor liver and poor early graft function may contribute to these posttransplant complications.

Vascular complications after pediatric liver transplantation from the living donors.

Early arterial or portal vein thrombosis is a complications that can lead to graft loss and patient death or need of immediate retransplantation. The aim of the study was to assess the incidence, causes, treatment, and outcome of vascular thrombosis after living related donor liver transplantation (LRdLTx). Between 1999 and 2004 71 LRdLTx were performed in children aged from 6 months to 10 years. Vascular thrombosis was found in 12 recipients. Hepatic artery thrombosis (HAT) occurred in 4 (5.6%), portal vein thrombosis (PVT) in 8 (11.2%) cases. HAT occurred 5 to 8 days, PVT 1 to 22 days after LTx. Diagnosis of vascular thrombosis was confirmed by routine Doppler ultrasound examination. Thrombectomy was successful in one patient with HAT and in three patients with PVT. Venous conduit was performed in one patient with PVT after second thrombosis. Two children developed biliary strictures as a late complication of HAT and required additional surgical interventions. Two children with PVT developed portal hypertension with esophageal bleeding, which required surgical intervention; one another underwent endoscopic variceal ligation for grade III varices. Follow-up ranged from 7 to 60 months. One patient died as a result of HAT after retransplantation due to multiple intrahepatic abscesses 2 months after first transplant. Any risk factors of vascular thrombosis that can be controlled should be avoided after transplantation. Routine posttransplant Doppler examination should be performed at least twice a day within 7 to 14 posttransplant days. Immediate thrombectomy should be always carried out to avoid late complications and even mortality.

Liver Transplantation in Polish Children With α1-Antitrypsin Deficiency: A Single-Center Experience.

BACKGROUND: α1-Antitrypsin deficiency (ATD) is the most common genetic cause of liver injury in young children. Asymptomatic hepatitis is observed in most patients. However, the course of liver disease due to ATD is unpredictable, and some children develop liver cirrhosis. Liver transplantation (Ltx) dramatically improves their outcome and in some cases is required in the first years of life. The aim of the study was to evaluate the course of the disease in children with ATD treated with Ltx in a single center. METHODS: We retrospectively reviewed the clinical features (ascites, esophageal varices, esophageal bleeding) and laboratory parameters of liver function in children with ATD who were treated with Ltx. RESULTS: Twenty-two Ltxs were performed in 20 children (13 boys, 7 girls). Median age at transplantation was 12 years (range 0.5 to 17.1). Four children were transplanted in the first 2 years of life and 16 patients were over 7 years old. The indications for Ltx in younger children were progressive cholestasis with coagulopathy and ascites. In older patients, the indications were as follows: liver failure presenting with variceal bleeding in 7 patients, ascites in 5 patients, hypersplenism in all but 1 patient. In the group of children transplanted over 7 years old, the frequency of cholestasis decreased intermittently in the second year of life: 4 patients (25%) compared to 15 patients (94%) and 10 patients (63%) in the neonatal and pretransplant period, respectively. In the group of children transplanted earlier, cholestasis and hepatitis were maintained until Ltx. Of transplanted patients, 50% were malnourished at the transplantation, and 50% were followed for more than 10 years. Five-year post-transplant survival was 100% (n = 14), and 10-year survival was 90%. Two patients died as adults with biliary post-transplant complications and problems with compliance. CONCLUSIONS: Our experience suggests that transient normalization of liver parameters in some patients with ATD do not exclude the liver disease progression to cirrhosis and unfavorable outcome of liver disease in childhood. In our group of patients, median age at transplantation was high compared to other centers. The long-term prognosis in children after transplantation is very good, but early post-transplant complications and probable problems with compliance in young adults may lead to graft failure.

Reduction of naive CD4/CD45RA+ T cells in children with biliary atresia before and after liver transplantation.

The aim of this study was to examine whether liver transplantation reverses the abnormal distribution of lymphocyte subsets previously observed in biliary atresia children, namely a selective decrease in the naive CD4/CD45RA+ T cell subset and an increase in the B and natural killer cell subpopulations. Eight biliary atresia children aged 1.08 to 6 years were studied before and 1 year after LTx for comparison with 15 age-matched healthy controls. The posttransplant immunosuppressive regimens included prednisone [0.1 mg/kg] and tacrolimus (level range: a 10-12 microg/dL). The percentage, absolute cell number, and receptor density were assessed by the use of double color flow cytometry (EPICS-XL MCL fluorocytometer). Biliary atresia patients were compared after LTx with subjects before LTx, essentially showing no statistically significant changes in lymphocyte subsets. We conclude that LTx of biliary atresia children does not reverse the abnormal lymphocyte subset distribution present before transplantation. Hence, these changes may reflect either their independence from the liver status or may result from immunosuppressive treatment that contributes to defective CD4+ T cell regeneration reflected by a deficiency in CD4/CD45RA+ naive T cells.

Bile duct variations in partial liver transplantations from living-related donors.

The aim of this paper was to present anatomic variations of bile ducts and their effect on the perioperative course of living-related donors in partial liver transplantations in children. Liver fragments for partial transplantation were harvested from 41 related donors. Segments II and III were harvested from 35 and segments II, III, and IV from 6 donors. During the procedure, cholangiography through cystic duct was performed revealing a normal anatomy of the bile ducts in 33 (80.5%) cases. The rest of the donors showed anatomic variations. There was only one case of complications related to the bile duct. The intraoperative diagnosis of anatomic variations allowed for safe partial liver harvesting.

Liver transplantation across ABO blood groups in children.

Late results after ABOI LTx are inferior to ABO compatible organs. We report seven patients who received LTx across ABO group for emergency indications. The blood type combinations were: A to O in three, B to O in two, and B to A in two. Episodes of acute and chronic rejection, immunosuppression, and biochemical and functional tests after transplantation as well as patient and graft survival were compared between ABOI group and patients with compatible ABO group transplanted due to FLF (group I) or in an elective setting (group II). Four children are alive. Two children died of sepsis and CNS damage or MOF, and one patient died during transplantation because of cardiac failure. All recipients of ABOI grafts received immunosuppression with cyclosporine or tacrolimus and steroids. MMF was added in two subjects, and induction with antilymphocyte globulins used in five patients. An acute rejection episode was diagnosed in two recipients between 7 and 11 days after LTx. All four living patients with ABOI grafts are doing well with follow-up time between 11 months and 5 years. In one patient PTLD occurred at 1 year after ABOI LTx but was cured by discontinuation of immunosuppression and administration of rituximab. Graft survival in the ABOI group was 57.1% versus 71% in group I and 73% in group II. Respective patients survival was 57.1% 71%, and 82.0% respectively. In conclusion, in urgent cases ABOI transplantation is justified in pediatric patients when compatible grafts are not available.

Rapamycin in children after liver transplantation.

Experience with sirolimus (SRL) in pediatric liver transplantation (LTx) is limited. The aim of the study was to present our experience with SRL in this setting. During the last 2 years we administered SRL to 9 LTx: children in 3 due to chronic rejection and 6 due to impaired renal function. SRL was started at 2 months to 2.5 years after LTx. Target trough levels for tacrolimus for patients with chronic rejection was 8 to 10 ng/mL and SRL 10 to 12 ng/mL; for patients with impaired renal function, 4 to 6 ng/mL and 8 to 10 ng/mL respectively. For patients on only SRL and steroids the target level was 12 to 20 ng/mL. Our observation on SRL varied from 3 to 21 months, including liver function, renal function, and side effects. All patients are alive. In 3 patients with chronic rejection (ChR), follow-up biopsies showed no signs of ChR; they all normalized liver biochemistry. Independent of indication all improved their renal function. Follow-up GFR in 5 patients showed significant improvement in all. All patients showed elevated serum cholesterol values. SRL was discontinued in 3 patients due to elevation of liver enzymes in 1, persistently high serum cholesterol in 1, and repeated bouts of opportunistic infection in 1. Addition of SRL with reduced doses of tacrolimus or switching to SRL alone significantly improves renal function.

Acute coagulopathy after reperfusion of the liver graft in children correction with recombinant activated factor VII.

BACKGROUND: Several studies have proven that massive blood loss increases postoperative morbidity and mortality in liver graft recipients. Since we have successfully corrected coagulopathy preoperatively using an intravenous (IV) bolus of recombinant activated factor VII (rFVIIa) in 2 patients with fulminant liver failure, we observed that there was rapid reversal of preexisting advanced coagulopathy in another 40 patients with high risk for intraoperative bleeding by this treatment immediately before transplantation. Recently to control hemostasis we have administered rFVIIa also to patients presenting with acute coagulopathy and nonsurgical bleeding after graft reperfusion as described herein. MATERIALS AND METHODS: We have used rFVIIa in 7 children presenting with severe coagulopathy and nonsurgical bleeding after liver graft reperfusion. The dosage of rFVIIa ranged between 37 and 148 mcg/kg. An antifibrinolytic agent (aprotinin, tranexamic acid) was administered simultaneously. RESULTS: APTT before rFVIIa was 86.10 to 183 seconds, (mean, 132.1 +/- 39.88), after the bolus of rFVIIa 49.4 to 206.1 (mean, 112.7 +/- 58.53), and at the end of surgery 71.70 to 180 (mean, 110.3 +/- 40.98). INR after reperfusion was 1.82 to 3.91 (mean, 2.56 +/- 0.67), 1.03 to 1.92 (mean, 1.54 +/- 0.35) after rFVIIa, and 1.74 to 5.58 (mean, 2.64 +/- 1.35) at the end of surgery. Before rFVIIa administration intraoperative blood transfusions after graft reperfusion were 900 to 4200 mL of red blood cells (RBC) (0.82-5.4 total blood volume) and after reperfusion 0 to 1800 mL of RBC (0-2.5 TBV). No postoperative vascular complications were observed. CONCLUSIONS: A single dose of rFVIIa effectively reverses the severe coagulopathy developing after graft reperfusion, establishing effective hemostasis in liver transplant recipients without an increased risk of thrombotic complications.

Autoimmune hepatitis in transplanted liver.

Liver transplantation is recognized as the appropriate treatment for end-stage liver disease. Four patients undergoing liver transplantation for classical end-stage liver disease developed de novo autoimmune hepatitis (AIH) in the graft. Recurrence of AIH after orthotopic liver transplantation and after reduction in immunosuppressive treatment is reported in one other patient. Markedly elevated serum transaminases were observed, together with an elevated serum IgG and/or globulin fraction and histological feature typical of AIH on liver biopsy.

Absence of teratogenicity of sirolimus used during early pregnancy in a liver transplant recipient.

We describe the case of successful delivery in a 21-year-old woman who became pregnant 3 years after liver transplantation and who received sirolimus during the first 6 weeks of gestation. Sirolimus was discontinued when ultrasonography revealed a pregnancy, she was switched to tacrolimus and prednisone was continued. The course of pregnancy was uneventful; there were no signs or symptoms of graft rejection. Due to fetal intrauterine threatening asphyxia the pregnancy was concluded by cesarean section in the 39th gestational week, delivering a healthy, 2950 g, Apgar 10, female infant.

Anatomical alteration of the vascular tree observed during living related liver transplantation.

INTRODUCTION: The number of available cadaveric donor organs has reached a plateau. One current solution has been to increase number of living related liver transplantations. MATERIAL AND METHODS: Since October 1999 in the Department of General, Transplant and Liver Surgery, Medical University of Warsaw, 40 living related liver transplantation have been carried out. RESULTS: In 31 (77.5%) cases, a normal arterial supply was observed: the common hepatic artery arose from a celiac trunk. In two cases (5.0%), there was a partial arterial blood supply by the right accessory hepatic artery originating from the superior mesenteric artery. In two cases (5.0%), a right hepatic artery arose completely from the superior mesenteric artery (replaced artery). In one case (2.5%), a common hepatic artery originated from the superior mesenteric artery. In two cases (5.0%), an accessory left segmental artery originated from the left gastric artery. In two cases (5.0%), the function of an absent left hepatic artery was assumed by a replaced left hepatic artery originating from the left gastric artery. In two (5.0%) cases, there were two separate ducts draining the right hemiliver. There were two (5.0%) cases of an accessory duct draining segment IV, originating within the confluence of the right and left hepatic ducts. In one (2.5%) case, the common hepatic duct showed a trifurcation. CONCLUSION: During harvesting from a living donor knowledge of anatomical variants must be used to optomize the liver graft.

Harvesting liver fragments from living-related donors: a single-center experience.

The aim of the study was to estimate the risk of harvesting a liver fragment from a living-related adult donor. Liver fragments were harvested from 44 donors. Liver segments II and III were harvested from 36 donors. Liver segments II, III, IV were harvested from 6 donors, 2 donors gave segments V, VI, VII, and VIII. After preliminary donor selection volumetric assessment of liver segments by computed tomography and arteriography was performed to visualize the cenac trunk and superior mesenteric artery. None of the donors died. No complications were observed during the operation. Only one case, a bile collection, was observed after surgery. We treated this patient with a satisfactory result by sonography-guided drainage. We observed temporary elevation of bilirubin and transaminase levels and a decrease in prothrombin index value. Blood transfusion was not necessary during any of the procedures. Mean hospitalization time after the surgery was 9.4 days. Mean graft weight/recipient weight ratio was 2.54%. The risk of the harvesting liver fragment from a living-related adult donor seems to be minimal.

Liver retransplantation in children in Poland.

An average of 15% of patients require retransplantation due to irreversible liver graft failure due to primary graft nonfunction, chronic rejection, vascular and biliary complications, or infections. The survival of patients and grafts after retransplantation is inferior to that after primary transplantation. The purpose of the present study was to examine the incidence, indications, and outcome of retransplantation in children. In our center 169 liver transplantations had been performed in 154 patients, and 14 patients (9%) required 15 retransplantations: nine in the early postoperative period, five late after primary transplantation, and one late after the second transplantation. One-year patient survival after primary transplantation was 82%, but after early retransplantation it was 55%.