Pediatric post‐transplant metabolic syndrome: New clouds on the horizon

Liver transplantation (LT) is a standard treatment for children with end‐stage liver disease, standing at more than 90% survival rate after one yr, and at over a 70% survival rate after five yr. The majority of transplanted children enjoy an excellent quality of life but complications can occur in the long term, and can develop subclinically in otherwise well children; there are various underestimated nutritional and metabolic aspects, including the so‐called post‐transplant metabolic syndrome (PTMS). During the post‐transplant period, the use of immunosuppressants, corticosteroids, calcineurin inhibitors, and the presence of risk factors, including non‐alcoholic fatty liver disease (NAFLD), and kidney and bone complications have been largely implicated in PTMS development. Strategies to reduce the progression of PMTS should include careful screening of patients for diabetes, dyslipidemia, and obesity, and to support weight reduction with a carefully constructed program, particularly based on diet modification and exercise. With early identification and appropriate and aggressive management, excellent long‐term health outcomes and acceptable graft survival can be achieved.     

Clinical consequences of human herpesvirus‐6 DNAemia in peripheral blood in pediatric liver transplant recipients

The significance of HHV6 DNAemia after solid organ transplantation has not been fully determined. Our objectives were to determine the prevalence of HHV6 DNAemia in pediatric liver transplant recipients and to describe the associated clinical characteristics and outcomes. This was a retrospective case–control study. Eligible liver transplant patients aged ≤ 18 yr with HHV6 DNAemia were matched with two subjects without HHV6 DNAemia. Matching was by age ± 6 months. Among 154 subjects, 25 patients (16%) had HHV6 DNAemia detected by PCR in whole blood or plasma (M:F ratio = 0.9:1). While 28% of subjects with DNAemia (7/25) had symptoms consistent with HHV6 infection, active infection was detected in only four subjects (2.6% of liver transplant patients). The major symptoms/signs were fever, vomiting, lethargy, splenomegaly, bone marrow suppression, and elevated transaminases. The prevalence of DNAemia due to other herpesviruses in cases vs. controls was EBV 56% vs. 60%, CMV 12% vs. 12%, HHV7 20% vs. 12%; p value is not significant for all pairwise comparisons. HHV6 DNAemia in pediatric liver transplant patients is not an uncommon entity. While the clinical relevance is still not entirely established, active HHV6 infection and attributable symptoms are relatively rare.     

Epstein‐Barr viral load monitoring for diagnosing post‐transplant lymphoproliferative disorder in pediatric liver transplant recipients

This study aimed to investigate the incidence of PTLD in pediatric liver transplant recipients and the risk factors for the development of PTLD. We also determined clinically useful quantitative EBV PCR parameters for aiding in the diagnosis of EBV‐associated PTLD in the pediatric liver transplant recipients at our institute. We reviewed children < 18 years old who had undergone liver transplantations and quantitative analysis of whole blood EBV load at our institute from January 2006 to March 2015. A total of 142 liver transplant recipients were included, and their median age was 1.5 years. Clinically significant high‐level EBV DNAemia ≥ 10 000 copies/mL at least twice was observed in 53.5% and PTLD occurred in 9.9%. Among PTLD group, graft failure and mortality rate were as high as 21.4% and 14.3%, respectively. Deceased donor, presence of high‐level EBV DNAemia, and primary CMV infection following transplant were associated with an increased risk for PTLD in the multivariate analysis. The peak titer at 10 875 copies/mL could be used as a cutoff value with a sensitivity of 92.9% and a specificity of 37.9%; the rate of increase in EBV load suggested a sensitivity of 64.3% and a specificity of 70.9% at the cutoff value of 44 000 copies/mL/week. In conclusion, the incidence of PTLD following liver transplant in children was as high as 10%. PTLD is associated with significant morbidity and mortality. Close monitoring of EBV DNAemia is crucial for the early diagnosis and proper treatment of PTLD in pediatric liver transplant recipients.     

Castleman disease in a pediatric liver transplant recipient: a case report and literature review

Castleman disease is a rare hematologic disorder, closely linked to the HHV-8, and most commonly observed in immunocompromised individuals. Thirteen months following a liver transplant for CPS-1 defect, a 15-month-old boy presented with fevers, anemia, and growth retardation. Abdominal CT scan showed splenomegaly and generalized lymphadenopathy. Histology of chest wall lymph nodes revealed a mixed CD3+ T-cell and CD20+ B-cell population with atretic germinal centers consistent with multicentric Castleman disease. Qualitative DNA PCR detected HHV-8 in the resected lymph node and in the blood, supporting the diagnosis. Immunosuppression was tapered, and he was transitioned from tacrolimus to sirolimus. His graft function remained stable, and repeat imaging showed regression of the lymphadenopathy. The child is living one yr after Castleman disease diagnosis with a well-functioning graft. Castleman disease is a potential complication of solid organ transplant and HHV-8 infection. Reduction in immunosuppression and switch to sirolimus may be an effective strategy to treat this condition.     

Long‐term outcomes of pediatric kidney transplant recipients with a pretransplant malignancy

A childhood malignancy can rarely progress to ESRD requiring a KT. To date, few reports describe long‐term outcomes of pediatric KT recipients with a pretransplant malignancy. Between 1963 and 2015, 884 pediatric (age: 0‐17 years old) recipients received 1055 KTs at our institution. KT outcomes were analyzed in children with a pretransplant malignancy. We identified 14 patients who had a pretransplant malignancy prior to KT; the majority were <10 years old at the time of KT. Ten (71%) patients received their grafts from living donors, the majority of which were related to the recipient. Wilms' tumor was the dominant type of pretransplant malignancy, seen in 50% of patients. The other pretransplant malignancy types were EBV‐positive lymphoproliferative disorders, non‐EBV‐positive lymphoma, leukemia, neuroblastoma, soft‐tissue sarcoma, and ovarian cancer. Ten of the 14 patients received chemotherapy as part of their pretransplant malignancy treatment. Graft survival at 1, 3, and 5 years was 93%, 83%, and 72%, respectively. Patient survival at 1, 5, and 10 years was 100%, 91%, and 83%, respectively. Six (40%) patients suffered AR following KT; half of them had their first episode of AR within 1 month of KT. Our single‐center experience demonstrates that pediatric KT recipients with a previously treated pretransplant malignancy did not exhibit worse outcomes than other pediatric KT patients.     

Liver abnormalities and post‐transplant survival in pediatric Fontan patients

The impact of liver parenchymal abnormalities on survival post‐heart transplant remains unknown in pediatric Fontan patients. We assessed pediatric Fontan patients who underwent heart transplant and had documented pretransplant hepatic ultrasound (U/S) studies. Liver U/S findings were classified as normal (Group 1), mildly abnormal (Group 2, hepatomegaly/vascular congestion), or severely abnormal (Group 3, heterogeneous echotexture/nodularity). Among 30 study patients, 8 were classified as Group 1, 14 as Group 2, while 8 met Group 3 criteria. Pretransplant liver biochemistry and synthetic function were similar in all groups. Six Group 3 patients underwent liver biopsy; 4 demonstrated perisinusoidal or centrilobular fibrosis, and 2 had cirrhosis. Overall mortality was 30% (n = 9). Median follow‐up was 5 years (range, 0.25‐13 years). One‐year survival was similar among all 3 groups (P = .37), with a trend toward higher cumulative 5‐year survival in Group 1 (100%). The majority of pediatric Fontan patients who underwent heart transplant demonstrated abnormal preoperative liver ultrasound findings. Heterogeneous echotexture or nodularity detected on U/S frequently indicates underlying liver parenchymal abnormalities. The presence of severe liver abnormalities was not associated with higher early mortality post‐heart transplant in pediatric Fontan patients; however, late outcomes must be further elucidated.     

Human herpesvirus type 8 infections among solid organ transplant recipients

Human herpes virus 8 (HHV-8) is known to be associated with Kaposi's sarcoma (KS), primary effusion lymphoma (PEL) and a form of Castleman's disease. Recently, it has also been shown to be associated with acute bone marrow failure in transplant patients. While, the full spectrum of clinical manifestations due to HHV-8 is yet to be defined in transplant recipients, it is known to cause post-transplant KS as a result of primary as well as secondary infection. This review will discuss the possible role of HHV-8 as a cause of disease in solid organ transplant recipients by focussing on important issues, including the biology of the virus, epidemiology, clinical manifestations, laboratory diagnosis and treatment, followed by a discussion of issues of relevance to the pediatric transplant recipient.     

Use of belatacept to maintain adequate early immunosuppression in calcineurin‐mediated microangiopathic hemolysis post‐renal transplant

We report a 17‐yr‐old boy who developed a microangiopathic hemolytic anemia presumed secondary to tacrolimus shortly following a living‐related donor renal transplant. This was initially managed by plasmapheresis. Reinstitution of calcineurin inhibition using cyclosporine led to recurrence of hemolysis, so an alternative agent was needed. He was commenced on monthly intravenous belatacept, with no further recurrence of the hemolysis, and subsequent stable graft function. Modulation via CTLA‐4 offers an alternative immunosuppressive tactic if current regimens produce graft threatening adverse effects. The method of administration and frequency of dosage of belatacept also lends itself well to the high‐risk period of adolescence and transition. We propose that belatacept may therefore also have utility in difficult cases complicated by poor concordance, common in the adolescent age group.     

Extended follow‐up of pediatric liver transplantation patients receiving once daily calcineurin inhibitor

We describe longitudinal results in a cohort of pediatric liver transplant patients successfully minimized to once daily CNI monotherapy for longer than five yr and assess changes in liver biochemistries and liver histology. A retrospective chart review of all pediatric liver transplant patients at a single center was performed. Biopsies and serum biochemistries (AST, ALT, total bilirubin, direct bilirubin, INR, creatinine) are reported at time points: PM, five‐yr, seven‐yr, and nine‐yr post‐minimization. Biopsies were assessed for inflammation and fibrosis using Ishak and Batts grading systems. Successful minimization to daily CNI monotherapy was defined as normal liver enzymes with no episodes of rejection. Thirty‐three patients have successfully remained on once daily CNI for >5 yr, and 19/33 of these patients have serial liver biopsies available for review. We report on the clinical and histological findings of these 19 patients. All 19 patients continue to have normal liver biochemistries. On post‐minimization biopsies, fibrosis progressed by ≥2 stages in one patient (5.3%) despite normal liver biochemistries. Carefully selected patients can tolerate minimization to once daily CNI monotherapy as few have progression of fibrosis.     

Early post‐operative intravenous tacrolimus in pediatric liver transplant recipients is not superior to oral tacrolimus

We aimed to compare the early results of i.v. with p.o. TAC as a primary immunosuppressant in pediatric patients undergoing LT. This retrospective study enrolled 75 children who underwent LT and received TAC‐steroid regimens as a primary immunosuppressant between September 2011 and October 2015 at our institution. Thirty‐five recipients received TAC i.v. and 40 received TAC p.o. Early results were evaluated and compared, including ACR, EBV, or CMV infection; renal adverse effects; and hospital stay. Comparisons of 90‐day post‐transplant results showed that the rates of overall viral (74% vs 40% P < 0.002), EBV (46% vs 17.5% P < 0.008), and CMV (51% vs 30% P = 0.05) infections were significantly higher in the i.v. than in the p.o. group. Neither regimen has any adverse effects on renal function. There were no between‐group differences in ACR incidence and severity, serum creatinine concentration, and hospital stay. Patient and graft survival rates at 3 months and 1 year did not differ significantly between the two groups. Compared with p.o. treatment, i.v. administration of high TAC concentration did not have beneficial post‐transplant effects on ACR incidence and severity, while increasing the incidence of viral infections in pediatric LT.     

Percutaneous removal of biliary stones post‐liver transplant in a pediatric patient: Case report and review of the literature

This case report describes an 8‐year‐old girl who underwent a segmental LT for a primary diagnosis of citrullinemia at the age of 12 months. She presented with cholangitis secondary to stenosis of the biliary‐enteric anastomosis. MRI revealed dilatation of intrahepatic bile ducts associated with multiple stones. An endoscopic approach failed to decompress the bile ducts and remove the stones. A percutaneous approach was then undertaken. After placement of a temporary external biliary drain for 12 days, a 26 French sheath was placed to access the bile ducts. Using a 14Fr flexible cystoscope, 80%‐90% of the biliary stones were removed. This was followed by antegrade balloon dilatation of the biliary‐enteric anastomosis. Two months later, the procedure was repeated, resulting in complete clearance of the biliary stones. An internal‐external biliary drain was maintained in placed for 10 months. The patient has been asymptomatic, with no evidence of stone recurrence for 13 months after drain removal. Percutaneous biliary stone removal is commonly performed in adults with non‐transplanted livers, especially in complex cases, and has also been shown to be successful in the pediatric population. However, it is rarely reported in transplanted livers in adults, and to the best of our knowledge, no pediatric cases have been reported. This case illustrates that this technique can be successfully utilized in pediatric LT patients.     

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.     

Post‐transplant lymphoproliferative disorder in pediatric intestinal transplant recipients: A literature review

Intestinal transplantation is a successful treatment for children with intestinal failure, but has many potential complications. PTLD, a clinically and histologically diverse malignancy, occurs frequently after intestinal transplantation and can be fatal. The management of this disease is particularly challenging. The rejection‐prone intestinal allograft requires high levels of immunosuppression, a precondition for PTLD. While EBV infection clearly plays a role in disease pathogenesis, the relatively naïve immune system of children is another likely contributor. As a result, pediatric intestine recipients have a higher risk of developing PTLD than other solid organ recipients. Other risk factors for disease development such as molecular and genomic changes that precipitate malignant transformation are not fully understood, especially among children. Studies on adults have started to describe the molecular pathogenesis of PTLD, but the genomic landscape of the malignancy remains largely undefined in pediatric intestinal transplant patients. In this review, we describe what is known about PTLD in pediatric patients after intestinal transplant and highlight current knowledge gaps to better direct future investigations in the pediatric population.     

The changing face of post‐transplant lymphoproliferative disease in the era of molecular EBV monitoring

Kerkar N, Morotti RA, Madan RP, Shneider B, Herold BC, Dugan C, Miloh T, Karabicak I, Strauchen JA, Emre S. The changing face of post‐transplant lymphoproliferative disease in the era of molecular EBV monitoring.
Pediatr Transplantation 2010: 14:504–511. © 2010 John Wiley & Sons A/S. Abstract: Pediatric PTLD is often associated with primary EBV infection and immunosuppression. The aim was to retrospectively review the spectrum of histologically documented PTLD for two time intervals differentiated by changes in use of molecular EBV monitoring. Eleven of 146 patients (7.5%) in 2001–2005 (Era A) and 10 of 92 (10.9%) in 1993–1997 (Era B) were diagnosed with PTLD. The median age at liver transplantation (0.8 and 0.9 yr, respectively) and the median duration between liver transplant and diagnosis of PTLD (0.6 and 0.7 yr, respectively) were similar in both eras. However, patients in Era A presented with significantly less advanced histological disease compared to patients in Era B (p = 0.03). Specifically, nine patients (82%) in Era A had Pl hyperplasia/polymorphic PTLD, whereas in Era B, six had advanced histological disease (five monomorphic and one unclassified). Three transplant recipients in Era B died secondary to PTLD, whereas there were no PTLD‐related deaths in Era A (p = 0.03). Heightened awareness of risk for PTLD, alterations in baseline immunosuppression regimens, implementation of molecular EBV monitoring, pre‐emptive reduction in immunosuppression and improved therapeutic options may have all contributed to a milder PTLD phenotype and improved clinical outcomes.     

Donor‐to‐recipient weight ratio is a risk factor for hepatic artery thrombosis after whole‐liver transplantation in children under 25 kg

Hepatic artery thrombosis (HAT) following pediatric liver transplantation increases morbidity and risk of graft failure. We performed a retrospective chart review of all patients who underwent deceased‐donor liver transplantation from August 2002 to July 2016. Multi‐organ transplant recipients were excluded. We examined the incidence of HAT at our institution and sought to identify associated donor or recipient risk factors. A total of 127 deceased‐donor liver transplant patients with a median age of 1.7 years (IQR 0.67‐6.7) were identified. Of those, 14 developed HAT, all weighing under 25 kg. Among 100 patients under 25 kg, whole‐liver graft recipients had an odds ratio of 3.98 (95% confidence interval [CI]: 1.03, 15.34; P = .045) for developing HAT compared with split‐liver graft recipients. Within the whole‐liver recipient group under 25 kg, 11 patients developed HAT with a median donor‐to‐recipient ratio (DRWR) of 0.9 (IQR: 0.7‐1.2) compared with a median DRWR of 1.4 (IQR: 1.1‐1.9) for those who did not develop HAT. Multivariate analysis showed DRWR to be an independent risk factor for HAT in patients weighing under 25 kg who received whole organ grafts, with an odds ratio of 3.89 (95% CI: 1.43, 10.54; P = .008) for each 0.5 unit decrease in DRWR. Our results suggest that in recipients under 25 kg 1) split‐liver grafts may have a lower rate of HAT and 2) selecting whole organ donors with a higher DRWR may decrease the incidence of HAT.     

Prompt diagnosis and management of Epstein–Barr virus‐associated post‐transplant lymphoproliferative disorder and hemophagocytosis: A dreaded complication in a post‐liver transplant child

EBV‐associated PTLD is increasingly recognized as an important cause of morbidity and mortality in both solid organ and hematopoietic stem cell transplant recipients. Mortality rates due to PTLD and virus‐induced HLH are reported to be quite high. We report a case of EBV‐associated PTLD and HLH in a child after liver transplantation who was successfully managed due to timely intervention. This case highlights that measurement of EBV load by quantitative polymerase chain reaction assays is an important aid in the surveillance and diagnosis of PTLD and early detection of EBV‐induced PTLD, and aggressive treatment with rituximab is a key to survival in patients who have undergone liver transplantation.     

Low donor‐to‐recipient weight ratio does not negatively impact survival of pediatric heart transplant patients

Tang L, Du W, Delius RE, L’Ecuyer TJ, Zilberman MV. Low donor‐to‐recipient weight ratio does not negatively impact survival of pediatric heart transplant patients.
Pediatr Transplantation 2010: 14:741–745. © 2010 John Wiley & Sons A/S. Abstract: A major limitation to success in pediatric heart transplantation is donor organ shortage. While the use of allografts from donors larger than the recipient is accepted, the use of undersized donor grafts is generally discouraged. Using the UNOS database, we wanted to evaluate whether using smaller donor hearts affects the short‐ and long‐term survival of pediatric heart transplant patients. A retrospective analysis of data entered into the UNOS database from April 1994 to May 2008 was performed. Pediatric heart transplant recipients (ages 0–18 yr) with DRWR <2.0 were identified and divided into two groups: Low‐DRWR (<0.8) and Ideal‐DRWR (0.8–2.0). Patients’ demographics, pretransplant diagnoses, age at transplantation, severity of pretransplant condition, and rate of complications prior to hospital discharge after transplantation were noted. Fisher’s exact, chi‐square, and Wilcoxon rank sum tests were used to compare patients’ baseline characteristics. Kaplan–Meier curves and Cox proportional hazard regression were used to compare patients’ survival and to identify independent risk factors for outcomes. There were 3048 patients (204 with Low‐ and 2844 with Ideal‐DRWR). The Low‐ratio group patients were older (8.3 vs. 6.9 yr; p = 0.001), there was a slight male predominance in the Low‐DRWR group (p = 0.055). The Low‐DRWR group had longer transplant wait time than the Ideal‐DRWR group (97 vs. 85 days; p = 0.04). The groups did not differ in race, primary diagnoses, severity of pretransplant condition (medical urgency status, need for ventilation, inotropic support, ECMO, nitric oxide, or dialysis, the PVR for those with bi‐ventricular anatomy), or post‐transplant complications (length of stay, need for inotropic support, dialysis, and rate of infections). The Low‐DRWR patients had less episodes of acute rejection during the first‐post‐transplant month. Infants with DRWR 0.5–0.59 had lower 30‐day survival rate (p = 0.045). There was no difference in short‐ and long‐term survival between the patients with DRWR 0.6–0.79 and DRWR 0.8–2.0. Use of smaller allografts (DRWR 0.6–0.8) has no negative impact on the short‐ and long‐term survival of pediatric heart transplant patients.