Devastating outflow obstruction after pediatric split liver transplantation

Sakamoto S, Nakazawa A, Shigeta T, Uchida H, Kanazawa H, Fukuda A, Karaki C, Nosaka S, Kasahara M. Devastating outflow obstruction after pediatric split liver transplantation. Abstract: HVOO is a rare complication after pediatric LT, which may lead to graft failure. There are various causes of HVOO, such as mechanical anastomotic obstruction and SOS. A 10‐month‐old female underwent split LT from a deceased donor for ALF. Her postoperative course was uneventful. However, her liver function suddenly deteriorated a month later. A liver biopsy revealed centrilobular injury, and D‐US suggested outflow obstruction. Venography was performed to reveal hepatic venous narrowing inside the graft. She received another graft from a living donor because of progressive graft failure in spite of successful venoplasty with stent insertion. The macroscopic findings of the explanted graft did not show an anastomotic stricture of the hepatic vein, although the pathological findings revealed necrosis of the first graft due to SOS. SOS might cause severe consequences with concomitant mechanical outflow obstruction after pediatric LT.     

Basiliximab treatment for steroid‐resistant rejection in pediatric patients following liver transplantation for acute liver failure

An IL‐2 receptor antagonist, basiliximab, decreases the frequency of ACR in liver transplant (LT) recipients as induction therapy. The aim of this study was to evaluate the effectiveness of basiliximab against SRR as rescue therapy in pediatric LT patients with ALF. Forty pediatric ALF patients underwent LT between November 2005 and July 2013. Among them, seven patients suffering from SRR were enrolled in this study. The median age at LT was 10 months (6–12 months). SRR was defined as the occurrence of refractory rejection after more than two courses of steroid pulse therapy. Basiliximab was administered to all patients. The withdrawal of steroids without deterioration of the liver function was achieved in six patients treated with basiliximab therapy without patient mortality, although one patient developed graft loss and required retransplantation for veno‐occlusive disease. The pathological examinations of liver biopsies in the patients suffering from SRR revealed severe centrilobular injuries, particularly fibrosis within one month after LT. We demonstrated the effectiveness and safety of rescue therapy consisting of basiliximab for SRR in pediatric LT recipients with ALF.     

Hepatopulmonary syndrome associated with nodular regenerative hyperplasia after liver transplantation in a child

HPS is a significant complication of portal hypertension in children with chronic liver disease and is an established indication for LT. It is characterized clinically by the triad of pulmonary vascular dilatation causing hypoxemia in the setting of advanced liver disease. NRH, a cause of non‐cirrhotic portal hypertension, is characterized by diffuse benign transformation of the hepatic parenchyma into small regenerative nodules with minimal or no fibrosis. Development of NRH and HPS in pediatric LT recipients has not been reported, although occasional cases have been reported in adult LT recipients. In this report, we discuss a case of a three‐yr‐old male who developed HPS, two yr after LT. Pulmonary and cardiac causes for hypoxemia were ruled out by appropriate investigations including a chest X ray, echocardiogram, cardiac catheterization, and a CT angiographic study. The diagnosis of HPS was confirmed via bubble echocardiogram that demonstrated intrapulmonary shunting. Open liver biopsy revealed marked NRH. The patient underwent liver retransplantation that resulted in complete reversal of his pulmonary symptoms and normal oxygen saturations within three months after LT.     

Angiosarcoma successfully treated with liver transplantation and sirolimus

Malignant liver tumors represent approximately 1% of malignancies in children. HA is a high‐grade tumor of endothelial cells that is even more rare in the pediatric population. HA has a limited response to chemotherapy, radiation and resection with universal tumor recurrence with LT and nearly 100% mortality by 18 months. This is the first reported successful case of hepatic angiosarcoma in a child who was treated by LT in combination with sirolimus. Sirolimus antagonizes the mTOR pathway, which regulates cell proliferation, differentiation, and migration, and is being studied as an anti‐neoplastic agent for solid tumors.     

Association of post‐transplant donor‐specific HLA antibody with liver graft fibrosis during long‐term follow‐up after pediatric liver transplantation

The aim of this study was to evaluate the significance of post‐transplant DSA as a predictor of liver fibrosis during long‐term follow‐up after pediatric LT. We evaluated the histological findings in 18 LT recipients who underwent liver biopsy after DSA screening. Liver fibrosis was scored based on the METAVIR fibrosis staging. Patients were divided into 2 groups based on histological findings, and clinical characteristics among patients with liver fibrosis were assessed. Of 18 patients, 7 were included in the fibrosis group. No significant between‐group differences were found regarding peritransplant characteristics, including age, sex, primary disease, ABO incompatibility, and immunosuppressive regimen. Episodes of acute rejection and non‐adherence to immunosuppressive drugs were comparable between both groups. The MFI for anti‐DR DSA and positive rate were significantly higher in the fibrosis group (1655 vs 216; P = .019, 86% vs 27%; P = .012, respectively). MFI for anti‐DQ DSA was higher in the fibrosis group, but non‐significantly (2052 vs 384; P = .46). Post‐transplant anti‐DR DSA is associated with graft fibrosis during long‐term follow‐up. This finding seems useful for the implementation of valid histological examinations of liver grafts for patients with higher MFI, especially for anti‐DR DSA, after pediatric LT.     

Isolated liver transplantation in children with cystic fibrosis – An Australian experience

Nightingale S, O’Loughlin EV, Dorney SFA, Shun A, Verran DJ, Strasser SI, McCaughan GW, Jermyn V, Van Asperen P, Gaskin KJ, Stormon MO. Isolated liver transplantation in children with cystic fibrosis – An Australian experience.
Pediatr Transplantation 2010: 14:779–785. © 2010 John Wiley & Sons A/S. Abstract: CF liver disease is an uncommon indication for pediatric LT. Determining optimal timing and type (isolated liver versus multi‐organ) of transplantation for those with severe liver disease can be challenging and involves consideration of the extent of liver disease (PHT, synthetic dysfunction) and extrahepatic factors such as pulmonary function. We present the experience of isolated LT for CF at our center. Eight children received one allograft each (3.9% of all grafts). One‐ and four‐yr survivals are both 75%. The two deaths occurred within the first two months after LT, and in both cases, invasive fungal infections were implicated, one following treatment for acute severe rejection. All had significant PHT, and six had synthetic dysfunction. All had roux‐en Y biliary anastomoses and none developed long‐term biliary complications. Seven had pulmonary colonization with Pseudomonas aeruginosa and six with fungus at time of transplantation. Mean pre‐LT FEV1 was 80% (range 59–116%) predicted, and lung function post‐LT was stable. Isolated LT in children with CF is successful in those with relatively preserved pulmonary function, which does not appear to deteriorate as a consequence. Roux‐en Y biliary anastomosis and antifungal prophylaxis should be a part of management of these patients.     

Liver allograft pathology in healthy pediatric liver transplant recipients

Liver transplantation offers excellent results for children with end‐stage liver disease, and efforts should be directed toward maintaining long‐term graft health. We evaluate graft pathology in healthy pediatric transplant recipients with low‐maintenance immunosuppressive medications to assess whether protocol biopsies are helpful for adapting immunosuppression and protecting long‐term graft function. Liver biopsies were performed on 60 healthy pediatric liver transplant recipients, and histological findings were correlated with laboratory, serological, and radiological results. Fourteen patients (23%) were diagnosed with acute or early chronic rejection, and immunosuppressive medications were increased in these children. Liver function tests did not correlate with histological findings. The incidence of fibrosis was 36% in transplant recipients five or more years after liver transplantation. We observed an unexpectedly high prevalence of rejection and fibrosis in children with no laboratory abnormalities, which led to changes in their immunosuppressive medications. Scheduled biopsies appear to be useful in pediatric transplant recipients with low immunosuppressive medications for early detection of morphological changes in liver transplants. Further studies are needed to evaluate whether adaption of immunosuppression helps to reduce tissue damage and the incidence of allograft dysfunction in the long term.     

Obliterative portal venopathy: A histopathologic finding associated with chronic antibody‐mediated rejection in pediatric liver allografts

The significance of post‐transplant HLA DSA and chronic AMR in LT is an emerging field of study. Although OPV has previously been described as a histopathologic finding in DSA‐positive adult LT recipients, it was not included in the recent Banff criteria for chronic AMR. Our aim was to describe the association between OPV and chronic AMR in pediatric LT recipients. A retrospective review of 67 liver biopsies performed between November 2014 and April 2016 in 45 pediatric LT recipients identified four patients with OPV. Clinical status, liver biochemistry, the presence of DSA, and available non‐HLA antibody testing, as well as histopathologic features of chronic AMR, were assessed. All four patients with OPV had class II DSA and histopathologic features of chronic AMR based on the Banff criteria. Two patients were noted to have non‐HLA antibodies. Three patients are undergoing treatment with IVIG but have persistent DSA. Two patients have graft failure and are awaiting retransplantation. In conclusion, OPV is a histopathologic finding associated with chronic AMR in pediatric LT recipients. Further studies are needed to elucidate whether OPV is reversible and/or amenable to medical therapy.     

Transient elastography for non‐invasive evaluation of post‐transplant liver graft fibrosis in children

As graft survival in pediatric LT is often affected by progressive fibrosis, numerous centers carry out protocol liver biopsies. Follow‐up biopsy protocols differ from center to center, but all biopsies are progressively spaced out, as time from transplant increases. Therefore, there is a need for non‐invasive techniques to evaluate graft fibrosis progression in those children who have no clinical or serological signs of liver damage. Indirect markers, such as the APRI, should be relied on with caution because their sensitivity in predicting fibrosis can be strongly influenced by the etiology of liver disease, severity of fibrosis, and patient age. A valid alternative could be TE, a non‐invasive technique already validated in adults, which estimates the stiffness of the cylindrical volume of liver tissue, 100‐fold the size of a standard needle biopsy sample. The aims of this study were to evaluate the reliability of TE in children after LT and to compare both the TE and the APRI index results with the histological scores of fibrosis on liver biopsies. A total of 36 pediatric LT recipients were studied. All patients underwent both TE and biopsy within a year (median interval ‐0.012 months) at an interval from LT of 0.36 to 19.47 years (median 3.02 years). Fibrosis was assessed on the biopsy specimens at histology and staged according to METAVIR. There was a statistically significant correlation between TE stiffness values and METAVIR scores (P = .005). The diagnostic accuracy of TE for the diagnosis of significant fibrosis (F ≥ 2) was measured as the area under the curve (AUROC = 0.865), and it demonstrated that the method had a good diagnostic performance. APRI was not so accurate in assessing graft fibrosis when compared to METAVIR (AUROC = 0.592). A liver stiffness cutoff value of 5.6 kPa at TE was identified as the best predictor for a significant graft fibrosis (METAVIR F ≥ 2) on liver biopsy, with a 75% sensitivity, a 95.8% specificity, a 90% positive predictive value, and an 88.5% negative predictive value. These data suggest that TE may represent a non‐invasive, reliable tool for the assessment of graft fibrosis in the follow‐up of LT children, alerting the clinicians to the indication for a liver biopsy, with the aim of reducing the number of protocol liver biopsies.     

Basiliximab with delayed introduction of calcineurin inhibitors as a renal‐sparing protocol following liver transplantation in children with renal impairment

Renal impairment is frequently compromised in patients with end‐stage liver disease and is associated with increased long‐term mortality post‐LT. In contrast to CNI, basiliximab is an immunosuppressive agent with minimal nephrotoxic potential. This study reviews the experience of a single pediatric liver transplant center's renal‐sparing approach with the use of basiliximab and MMF to compensate for delayed entry of CNI in children with renal impairment at the time of organ availability. There were no differences in renal function between pediatric patients with and without pre‐LT renal impairment within the first year (cGFR: 135 mL/min/1.73 m² vs. 144 mL/min/1.73 m²; p = 0.56) or at 5–8 yr following LT, (129 mL/min/1.73 m² vs. 130 mL/min/1.73 m²; p = 0.97). In addition, there was no difference in ACR rates (50% vs. 43%, p = 0.62) between patients in the basiliximab group and those patients receiving standard CNI and steroid strategies. The utilization of a renal‐sparing approach with basiliximab alongside delayed entry and lower early target trough levels of CNI in children with renal impairment at the time of LT is safe and maintains excellent long‐term kidney function.     

Liver retransplantation in children: The Atlanta experience

Heffron TG, Pillen T, Smallwood G, Henry S, Sekar S, Solis D, Casper K, Fasola C, Romero R. Liver retransplantation in children: The Atlanta experience.
Pediatr Transplantation 2010: 14:417–425. © 2010 John Wiley & Sons A/S. Abstract: Liver retransplantation is routinely offered at our institution. Previous reports document that patient and graft survival is significantly less after pediatric rLT compared to primary LT. This has engendered intense debate regarding optimal allocation of organs. Here, we examine our program’s approach to pediatric hepatic retransplantation related to patient factors affecting outcomes. Between 1997 and 2009, 272 LTs were performed in 234 patients (mean survival 1994 ± 1367 days) at our center. Thirty‐four patients required rLT including 10 who received their primary transplant elsewhere and four who required two retransplantations. Patient survival did not differ significantly between rLT and LT at one and three yr (p = 0.56). Graft survival between rLT and LT was also similar (p = 0.606) at one and three yr. No significant difference in graft or patient survival was noted between: Patients retransplanted <30 days after LT vs. those >30 days (p = 0.152); patients transplanted with technical variants vs. whole grafts (p = 0.966); technical variants utilized for LT vs. rLT (p = 0.713); rLT recipient age (< or >5 yr; p = 0.298); or ABOI for rLT and LT (p = 0.650). Retransplantation should be offered to optimize pediatric recipient survival after LT and offers similar survival as primary transplant.     

Perioperative anticoagulation practices for pediatric liver transplantation

Despite continued advancements in perioperative care for pediatric liver transplant (LT), graft‐threatening vascular occlusion events including hepatic artery thrombosis (HAT) and portal vein thrombosis (PVT) remain a source of significant morbidity and mortality. Perioperative anticoagulation is commonly used for the prevention of HAT and PVT, but evidence‐based guidelines are lacking. The goals of this survey were to determine the frequency of use of an anticoagulation protocol and to describe variation in anticoagulation practices among pediatric LT centers. The study consisted of an online survey distributed to members of SPLIT. The survey focused on institutional anticoagulation practices employed to reduce the incidence of graft and life‐threatening vascular occlusion events. Responses were received from 31 of 39 SPLIT centers. All respondents report using anticoagulation after pediatric LT, and approximately 90% have institutional anticoagulation protocols. Subgroup analysis of high volume pediatric LT centers revealed similar variability in anticoagulation patterns. All participating SPLIT centers reported the use of post‐transplant anticoagulation and nearly all use a protocol. However, there is marked variability in the type and dose of anticoagulation as well as the timing of initiation and duration of therapy across centers.     

Technique advance to avoid hepatic venous outflow obstruction in pediatric living‐donor liver transplantation

HVOO represents a serious critical complication of pediatric living‐donor liver transplantation because open surgical repair is virtually impossible. Currently, despite several technical innovations and the introduction of triangulated anastomosis for hepatic vein reconstruction, the reported incidence of HVOO is still considerable. The aim of this study was to propose a new technique for hepatic venous reconstruction that avoids the original orifice of the recipient hepatic veins. Instead, anastomosis is performed in a newly created wide longitudinal orifice in the anterior wall of the recipient inferior vena cava. A total of 210 living related‐donor liver transplantations were performed using two methods for reconstruction of the hepatic vein. Group 1 included 69 patients subjected to direct anastomosis of the orifice of the graft hepatic vein and a wide orifice created in the recipient inferior vena cava by the confluence of the orifices of the right, left, and middle hepatic veins. Group 2 included 141 patients in whom the original orifices of the recipient hepatic veins were closed, the inferior vena cava was widely opened, and a long longitudinal anastomosis was performed using two lines of continuous sutures. Diagnosis of HVOO was suspected based on clinical findings and ultrasound studies and then confirmed by liver biopsy and interventional radiology examinations. Among the 69 recipients in group 1, 16 patients died due to graft problems during the postoperative period and eight of the survivors (15.1%) presented with HVOO. In group 2 (141 patients), 21 patients died, and there were no cases of HVOO. A comparison of the incidence of HVOO between groups revealed a significant difference (p = 0.01). Hepatic venous reconstruction during pediatric living‐donor liver transplantation should be performed using a wide longitudinal incision in the anterior wall of the recipient inferior vena cava because this technique eliminated anastomosis complications.     

The histological quantification of alpha‐smooth muscle actin predicts future graft fibrosis in pediatric liver transplant recipients

Activated hepatic stellate cells express cytoplasmic ASMA prior to secreting collagen and consequent liver fibrosis. We hypothesized that quantifying ASMA could predict severity of future fibrosis after LT. For this, 32 pairs of protocol biopsies, that is, “baseline” and “follow‐up” biopsies taken at 1‐ to 2‐year intervals from 18 stable pediatric LT recipients, transplanted between 2006 and 2012 were selected. Morphometric quantification of “ASMA‐positive area percentage” was performed on the baseline biopsy. Histological and fibrosis assessment using Metavir and LAFSc was performed on all biopsies. The difference of fibrosis severity between the “baseline” and “follow‐up” was termed “prospective change in fibrosis.” Significant association was seen between extent of ASMA positivity on baseline biopsy and “prospective change in fibrosis” using Metavir (P=.02), cumulative LAFSc (P=.02), and portal LAFSc (P=.01) values. ASMA‐positive area percentage >1.05 predicted increased fibrosis on next biopsy with 90.0% specificity. Additionally, an association was observed between extent of ASMA positivity and concomitant ductular reaction (P=.06), but not with histological inflammation in the portal tract or lobular area. Hence, ASMA quantification can predict the future course of fibrosis.     

Current status and actual need for pediatric liver transplantation in Southern Vietnam

Liver transplantation (LT) has considerably improved the outcome of patients with end‐stage liver disease, especially in children. The first pediatric LT in Vietnam was performed in 2004. To assess the current need for pediatric LT in Southern Vietnam, a total of 280 patients with chronic liver disease followed at Children's Hospital 2 (Ho Chi Minh City), the only pediatric LT center in this region, were evaluated from January 2009 to June 2014. Sixty‐seven patients satisfied criteria for LT but only one transplant surgery occurred since 2009. Parental consent for LT was obtained only in 28.4% of patients. The main reasons for the small number of LTs were financial costs, far distance from home, lifelong follow‐up and treatment, and shortage of organ donors. We conclude that the current need for pediatric LT in Southern Vietnam is high. Efforts should be made to develop the liver transplant program in this developing country.     

Transmission of clear cell tumor in a graft liver from cadaveric donor: Case report

Backes AN, Tannuri ACA, de Mello ES, Gibelli NEM, de Castro Andrade W, Tannuri U. Transmission of clear cell tumor in a graft liver from cadaveric donor: Case report. Abstract: Neoplasms in children after organ transplantation are related to the type and intensity of immunosuppression and the donor–recipient serostatus, especially in relation to the Epstein–Barr virus. The patient was a two‐yr‐old female child with biliary atresia who underwent a liver transplantation from a female cadaver donor. Two adults received kidney transplants from the same donor. Nine months after transplantation, one of the adult recipients developed an urothelial tumor in the kidney graft. Imaging tests were repeated monthly in the liver‐transplanted child and revealed no abnormalities. However, one yr and two months after the transplantation, the patient developed episodes of fever. At that time, imaging and liver biopsy showed a clear cell tumor of urothelial origin in the graft and the disease was limited to the liver. The patient underwent liver retransplantation, and she is currently free of tumor recurrence. Although rare, the occurrence of tumors in the post‐transplant period from cadaver donors, without previously diagnosed tumors, is one of the many problems encountered in the complex world of organ transplantation.     

Incidence,impact, and treatment of portal and hepatic venous complications following pediatric liver transplantation: A single‐center 12 year experience

Heffron TG, Pillen T, Smallwood G, Henry S, Sekar S, Casper K, Solis D, Tang W, Fasola C, Romero R. Incidence, impact, and treatment of portal and hepatic venous complications following pediatric liver transplantation: A single‐center 12 year experience.
Pediatr Transplantation 2010: 14:722–729. © 2010 John Wiley & Sons A/S. Abstract: PVT or PVS and HVOO are known causes of graft and patient loss after pediatric liver transplantation. Increased incidences of these complications have been reported in partial livers including DDSLT or LDLT. From 1997 to 2008, 241 consecutive pediatric patients received 271 hepatic grafts at a single center. Median follow‐up is 1856 days. Surgical technique, demographics, lab values, and radiologic imaging procedures were obtained utilizing OTTR^® to evaluate the relationship of portal and hepatic complications with risk factors, patient and graft survival. Grafts were composed of 115/271 (42.4%) partial livers of which 90 (33.2%) were DDSLT and 25 (9.2%) LDLT. Of 271 patients, 156 (57.6%) received whole‐sized grafts. There were six PVC in five patients with one patient requiring retransplantation (0.34%) and no patient deaths. Utilizing all three hepatic vein orifices on the recipient hepatic vena cava and the donor hepatic vein cut short enables a wide hepatic outflow tract unlikely to twist. None of the 241 patients developed early or late complications of the hepatic vein. None of the last 128 consecutive patients who received 144 grafts over seven and a half yr have developed either early or late complications of the hepatic or portal vein. Partial‐graft actuarial survival was similar to whole‐graft survival (87.2% vs. 85.3% at one yr; 76.6% vs. 80.2 at three yr; p = 0.488). Likewise, patient survival was similar between partial grafts and whole grafts (93.8% vs. 93.1% at one yr; 89.8% vs. 87.2% at three yr; p = 0.688) with median follow‐up of 1822 (±1334) days. Patients receiving partial livers were significantly younger and smaller than patients receiving whole livers (p < 0.001). Portal and hepatic venous complications may have negative effects on patient or graft survival after pediatric liver transplantation. In our series, there was one graft and no patient loss related to portal or hepatic venous complications after pediatric liver transplantation over 12 yr.     

Outcomes and technical aspects of liver retransplantation with living donors in children

Re‐LT is the only recourse for patients with liver graft failure. However, survival rates after re‐LT are lower than those of primary transplants. Few reports are available regarding re‐LT with LDs in children. The objective of this study was to describe our cohort of patients retransplanted with LD and emphasize the technical aspects of a re‐LT with LD. This is a retrospective report of a series of 18 children (<18 yr old) submitted to 20 re‐LT from January 1997 to December 2013 at Hospital Sirio‐Libanes and Hospital AC Camargo Cancer Center. The one‐ and five‐yr survival for patients retransplanted with LD was 70.6% and 58.6%. Little technical modifications from a regular LD primary transplant were needed in patients retransplanted with LD. Seven (38.8%) patients presented vascular complications following re‐LT and three presented biliary complications (16.6%). In conclusion, a re‐LT with LD is an acceptable alternative for children who experience liver graft failure and it does not compromise the donor pool. Further experience with re‐LT with LD may support this therapy.     

Percutaneous transhepatic venous angioplasty in a two-yr-old patient with hepatic vein stenosis after partial liver transplantation

We report one case of severe hepatic vein stenosis, in a two-yr-old pediatric patient with a left lateral split liver transplantation (S2-S3) and severe ascites, in whom color Doppler ultrasound failed to make the diagnosis and transhepatic balloon angioplasty was successfully performed.     

Meso-Rex shunt for immediate portal revascularization in pediatric liver transplantation: first report

We describe the case of a 13-month-old girl transplanted for biliary atresia with PV hypoplasia. She received the left liver lobe of her mother and presented intraoperative portal thrombosis. Because of technical reasons, the opportunity to have conventional PV reconstruction using the donor left PV stump was lost. Immediate conversion to a meso-Rex shunt, using the recipient jugular vein as a bridge between the superior mesenteric vein and the graft Rex recessus, allowed excellent portal revascularization of the transplant. We suggest that synchronous meso-Rex shunt may constitute a valid alternative to truncal PV anastomosis during pediatric LT.