Anti-HLA antibodies and especially donor-specific antibodies (DSA) play a significant role in graft survival after solid organ transplantation. Their impact on long-term survival in adult liver ...transplantation (LT) is controversial, but they may be a risk factor. The effects of DSA after pediatric LT are still unclear.
We performed a retrospective evaluation of DSA in sera from 43 children who had received transplants at our tertiary center. Twenty-four patients had good long-term clinical and laboratory graft function (group 1), whereas 19 LT recipients suffered from histologically confirmed and clinically relevant chronic allograft rejection (group 2); 16 of these have already undergone retransplantation due to graft dysfunction. Inclusion criteria were availability of sera before the first LT to identify preformed antibodies in case of DSA positivity after LT and long-term follow-up at our institution. Sera were analyzed for anti-HLA antibodies using Luminex single antigen beads, where a mean fluorescence intensity value of more than 1500 was considered positive.
The prevalence of DSA was 33% for group 1 and 68% for group 2. Antibodies were predominantly HLA class II. Values of mean fluorescence intensity were comparable in both groups. Only one of the DSA+ ve patients from group 1 exhibited preformed antibodies. In conclusion, pediatric patients with chronic rejection revealed a higher rate of de novo DSA, especially of HLA-class II DSA. Further studies are necessary to confirm these data with a larger pediatric cohort.
Progressive familial intrahepatic cholestasis type 2 (PFIC‐2) is caused by mutations in ABCB11, encoding the bile salt export pump (BSEP). In 2009, we described a child with PFIC‐2 who developed ...PFIC‐like symptoms after orthotopic liver transplantation (OLT). BSEP‐reactive antibodies were demonstrated to account for disease recurrence. Here, we characterize the nature of this antibody response in 7 more patients with antibody‐induced BSEP deficiency (AIBD). Gene sequencing and immunostaining of native liver biopsies indicated absent or strongly reduced BSEP expression in all 7 PFIC‐2 patients who suffered from phenotypic disease recurrence post‐OLT. Immunofluorescence, western blotting analysis, and transepithelial transport assays demonstrated immunoglobulin (Ig) G‐class BSEP‐reactive antibodies in these patients. In all cases, the N‐terminal half of BSEP was recognized, with reaction against its first extracellular loop (ECL1) in six sera. In five, antibodies reactive against the C‐terminal half also were found. Only the sera recognizing ECL1 showed inhibition of transepithelial taurocholate transport. In a vesicle‐based functional assay, transport inhibition by anti‐BSEP antibodies binding from the cytosolic side was functionally proven as well. Within 2 hours of perfusion with antibodies purified from 1 patient, rat liver showed canalicular IgG staining that was absent after perfusion with control IgG. Conclusions: PFIC‐2 patients carrying severe BSEP mutations are at risk of developing BSEP antibodies post‐OLT. The antibody response is polyclonal, targeting both extra‐ and intracellular BSEP domains. ECL1, a unique domain of BSEP, likely is a critical target involved in transport inhibition as demonstrated in several patients with AIBD manifest as cholestasis. (Hepatology 2016;63:524–537)
(1) Background: Accurate hepatic artery (HA) depiction following pediatric liver transplantation (LT) is essential for graft surveillance but challenging on ultrasound (US). This study assesses if ...improved HA delineation can be achieved by recording two-dimensional US volumes in Color Doppler (CD) and B-flow technique. (2) Methods: Of 42 consecutive LT, 37 cases were included, and HA delineation was retrospectively rated using a four-point score (0 = HA not detectable, 3 = HA fully detectable, separable from portal vein) within 48 h post-LT (U1) and before discharge (U2). (3) Results: Adding B-flow compared with CD alone showed superior results at neohilar (U1: 2.2 ± 1.0 vs. 1.1 ± 0.8,
< 0.0001; U2: 2.5 ± 0.8 vs. 1.5 ± 0.9,
< 0.0001) and segmental levels (U1: 2.8 ± 0.6 vs. 0.6 ± 0.8,
< 0.0001; U2: 2.8 ± 0.6 vs. 0.7 ± 0.5,
< 0.0001). (4) Conclusions: Standardized US volume recordings combining B-flow and CD can effectively delineate the HA along its vascular course in pediatric LT. The technique should be further evaluated as a standard monitoring instrument to rule out vascular complications after LT.
In contrast to adult-onset inflammatory bowel disease (IBD), where many genetic loci have been shown to be involved in complex disease etiology, early-onset IBD (eoIBD) and associated syndromes can ...sometimes present as monogenic conditions. As a result, the clinical phenotype and ideal disease management in these patients often differ from those in adult-onset IBD. However, due to high costs and the complexity of data analysis, high-throughput screening for genetic causes has not yet become a standard part of the diagnostic work-up of eoIBD patients.
We selected 28 genes of interest associated with monogenic IBD and performed targeted panel sequencing in 71 patients diagnosed with eoIBD or early-onset chronic diarrhea to detect causative variants. We compared these results to whole-exome sequencing (WES) data available for 25 of these patients.
Target coverage was significantly higher in the targeted gene panel approach compared with WES, whereas the cost of the panel was considerably lower (approximately 25% of WES). Disease-causing variants affecting protein function were identified in 5 patients (7%), located in genes of the IL10 signaling pathway (3), WAS (1), and DKC1 (1). The functional effects of 8 candidate variants in 5 additional patients (7%) are under further investigation. WES did not identify additional causative mutations in 25 patients.
Targeted gene panel sequencing is a fast and effective screening method for monogenic causes of eoIBD that should be routinely established in national referral centers.
Immunosuppression after pediatric liver transplantation remains a major challenge. MTOR inhibitors provide a promising therapeutic approach in combination with reduced CNI after transplantation. ...However, there are still few data regarding their use in children.
We analyzed 37 patients with a median age of 10 years, who received Everolimus for one or more of the following indications: I = chronic graft dysfunction (
= 22); II = progressive renal impairment (
= 5); III = non-tolerable side effects with previous immunosuppressive medication (
= 6); and IV = malignancies (
= 10). The median follow-up time was 36 months.
Patient survival was 97%, and graft survival 84%, respectively. Stabilization of graft function was observed in 59% in subgroup 1, with 18.2% ultimately requiring retransplantation. No patient in subgroup IV developed recurrence of his primary tumor or PTLD by the endpoint of the study. Side effects were observed in 67.5% of the study patients, with infections being the most frequent (
= 20; 54.1%). There were no relevant effects on growth and development.
Everolimus seems to be a treatment option in selected pediatric liver graft recipients for whom other regimens are not suitable. Overall, the efficacy was good and the side effect profile appeared to be acceptable.
Combined or sequential liver and kidney transplantation (CLKT/SLKT) restores kidney function and corrects the underlying metabolic defect in children with end-stage kidney disease in primary ...hyperoxaluria type 1 (PH1). However, data on long-term outcome, especially in children with infantile PH1, are rare.
All pediatric PH1-patients who underwent CLKT/SLKT at our center were analyzed retrospectively.
Eighteen patients (infantile PH1
= 10, juvenile PH1
= 8) underwent transplantation (CLKT
= 17, SLKT
= 1) at a median age of 5.4 years (1.5-11.8). Patient survival was 94% after a median follow-up of 9.2 years (6.4-11.0). Liver and kidney survival-rates after 1, 10, and 15 years were 90%, 85%, 85%, and 90%, 75%, 75%, respectively. Age at transplantation was significantly lower in infantile than juvenile PH1 (1.6 years (1.4-2.4) vs. 12.8 years (8.4-14.1),
= 0.003). Median follow-up was 11.0 years (6.8-11.6) in patients with infantile PH1 vs. 6.9 years (5.7-9.9) in juvenile PH1 (
= 0.15). At latest follow-up kidney and/or liver graft loss and/or death showed a tendency to a higher rate in patients with infantile vs. juvenile PH1 (3/10 vs. 1/8,
= 0.59).
In conclusion, the overall patient survival and long-term transplant outcome of patients after CLKT/SLKT for PH1 is encouraging. However, results in infantile PH1 tended to be less optimal than in patients with juvenile PH1.
Infantile hepatic hemangioma, the most common vascular tumor of the liver in infancy, can occur with acute postnatal liver and congestive heart failure. Nevertheless, its course is often benign, and ...many children can be diagnosed and treated without surgical intervention. The distinction from malignant diseases is not always easy and it not clear whether invasive procedures for diagnosis and therapy should be performed. Here we report our experiences in our Center for Pediatric Liver Disease and postulate that large studies are needed to avoid unnecessary invasive procedures for these patients in the future.
AARS1 deficiency belongs to the group of disorders affecting aminoacyl-tRNA synthetases. To date, AARS1 deficiency has only been linked to neurologic disorders. We report a 6-year-old girl with ...microcephaly and developmental delay who presented with repeated episodes of acute liver failure. Whole-exome sequencing revealed compound heterozygosity for two missense variants within the AARS1 gene, p.Leu298Gln;Arg751Gly), whose functional relevance was demonstrated by decreased enzymatic activity in fibroblasts. This is the first report that shows that AARS1 variants may be associated with recurrent acute liver failure.
Zusammenfassung
Ziliopathien sind heterogene, genetisch determinierte Erkrankungen und betreffen häufig unterschiedliche Organsysteme. Patient:innen mit Zystennieren weisen häufig eine extrarenale ...Beteiligung wie z. B. eine kongenitale Leberfibrose, Choledochuszysten oder ein Caroli-Syndrom auf. Zu den häufigsten Zystennieren gehören die autosomal-rezessive (ARPKD) und die autosomal-dominante polyzystische Nierenerkrankung (ADPKD) sowie der Formenkreis der Nephronophthise (NPHP), die alle mit einer extrarenalen Symptomatik assoziiert sein können („nephronophthisis-related ciliopathies“, NPHP-RC). Bei der ARPKD findet sich eine obligate kongenitale Leberfibrose mit portaler Hypertension, bei der ADPKD entwickeln sich Leberzysten und bei Patient:innen mit Nephronophthise neben der Fibrose und Zystenbildung auch häufig ein hepatischer Juckreiz. Zusätzlich gibt es diverse seltene syndromale Erkrankungen aus dem Formenkreis der Ziliopathien, die sowohl einen renalen als auch einen hepatischen Phänotyp aufweisen können. Bei Vorliegen einer polyzystischen Nierenerkrankung mit hepatobiliärer Beteiligung sollte eine interdisziplinäre Betreuung Standard sein, da häufig weitere Organsysteme betroffen sind. Die portale Hypertension mit der Ausbildung von Varizen kann mit schweren Komplikationen einhergehen. Der hepatische Juckreiz kann die Lebensqualität dieser Patient:innen schwer beeinträchtigen. Neben symptomatischen Therapieansätzen ist im Einzelfall eine Lebertransplantation zu erwägen.
We present a 4‐year‐old boy admitted to the hospital due to the typical symptoms of celiac disease with severe dystrophy, anaemia and elevated gliadin IgG antibodies. Upper endoscopy ruled out celiac ...disease but showed severe Candida esophagitis. Due to an impaired T‐cell function especially following Candida antigen stimulation in vitro, plus recurrent Candida infections of the skin, the diagnosis of chronic mucocutaneous candidasis (CMC) was made. Under the treatment with fluconazol, trimethoprim/sulfmethoxazole and IVIG, the child improved impressively. Gliadin antibodies declined steadily.
Conclusion: The common symptoms growth retardation, anaemia and elevated gliadin antibodies are suggestive for celiac disease but very unspecific. The rare immunodeficiency CMC may cause elevated gliadin antibodies.
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